Background and Aims Retroperitoneal liposarcoma is a rare type of soft tissue sarcoma with low incidence, poor prognosis, and limited treatment options. The prognosis of patients with different pathological types is quite different, and there is a lack of large sample clinical research evidence for this group of patients. So, the clinical individualized treatment plan is difficult to establish. The purpose of this study was to explore the prognostic factors for patients with different pathological types of retroperitoneal liposarcoma, and to determine the application values of surgery, radiotherapy and chemotherapy for them.Methods The data of patients with retroperitoneal liposarcoma diagnosed by pathology and with complete follow-up record from 1975 to 2016 were retrieved from the SEER database, and the eligible cases were selected according to the inclusion and exclusion criteria. Using the ICD-O-3 classification, the patients were divided into five types that included well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid/round cell liposarcoma, pleomorphic liposarcoma and mixed liposarcoma. The differences of cancer-specific survival (CSS) and overall survival (OS) among patients with different pathological types were compared. The influencing factors for CSS and OS of the patients were analyzed.Results A total of 2 296 patients with retroperitoneal liposarcoma were included. Of them, 917 cases were well-differentiated liposarcoma, 847 cases were dedifferentiated liposarcoma, 302 cases were myxoid/round cell liposarcoma, 135 cases were pleomorphic liposarcoma and 95 cases were mixed liposarcoma. The median follow-up was 42 months (IQR: 13~90 months). The estimated 5-year OS were 74.99% (95% CI=71.65-78.01) for well-differentiated liposarcoma, 42.83% (95% CI=38.87-46.73) for dedifferentiated liposarcoma, 50.13% (95% CI=47.02-58.86) for myxoid/round cell liposarcoma, 34.69% (95% CI=26.39-43.11) for pleomorphic liposarcoma, and 57.67% (95% CI=46.43-67.37) for mixed liposarcoma, respectively. Log-rank test showed that difference was statistically significant among them (χ²=211.54, P<0.0001). The estimated 5-year CSS were 87.98% (95% CI=85.23-90.25) for well differentiated liposarcoma, 57.78% (95% CI=50.46-61.85) for dedifferentiated liposarcoma, 64.99% (95% CI=58.64-70.62) for myxoid/round cell liposarcoma, 46.02% (95% CI=36.22-55.25%) for pleomorphic liposarcoma, 67.33% (95% CI=55.71-76.53) for mixed liposarcoma, respectively. Log-rank test showed that the difference was statistically significant among them (χ²=227.92, P<0.000 1). Cox multivariate analysis of different pathological types showed that age was an independent factor affecting the prognosis of patients of all pathological types (all P<0.05). In well-differentiated liposarcoma patients, both radical and non-radical operation improved the OS (radical operation: HR=0.42, 95% CI=0.19-0.92, P=0.031; non-radical operation: HR=0.40, 95% CI=0.18-0.88, P=0.023) and CSS (radical operation: HR=0.32, 95% CI=0.16-0.63, P=0.001; non-radical operation: HR=0.23, 95% CI=0.12-0.44, P=0.001); chemotherapy reduced the OS (HR=2.29, 95% CI=1.54-3.40, P<0.001) and CSS (HR=3.55, 95% CI=2.16-5.83, P<0.001). In dedifferentiated liposarcoma patients, both radical and non-radical operation improved the OS (radical operation: HR=0.25, 95% CI=0.18-0.35, P<0.001, non-radical operation: HR=0.34, 95% CI=0.24-0.47, P<0.001) and CSS (radical operation: HR=0.22, 95% CI=0.15-0.33, P<0.001; non-radical operation: HR=0.31, 95% CI=0.21-0.45, P<0.001); radiotherapy improved the CSS (HR=0.75, 95% CI=0.57-0.99, P=0.043); chemotherapy reduced the OS (HR=1.33, 95% CI=1.05-1.69, P=0.018) and CSS (HR=1.64, 95% CI=1.24-2.18, P=0.001). Radiotherapy improved the OS (HR=0.66, 95% CI=0.47-0.92, P=0.015) and CSS (HR=0.54, 95% CI=0.34-0.84, P=0.007) in patients with myxoid/round cell liposarcoma.Conclusion Age is an independent risk factor affecting the prognosis of patients with different pathological types of retroperitoneal liposarcoma. For the treatment of retroperitoneal liposarcoma, individualized treatment should be made under the guidance of pathological classification. Surgical resection is the best treatment for well differentiated and dedifferentiated liposarcoma. For the choice of surgical methods, the general condition of the patients should be comprehensively evaluated. R₀ resection is not necessary in patients with well-differentiated liposarcoma. R₁ resection or local treatment (including microwave, radiofrequency, etc.) can also improve the OS and CSS in patients with well-differentiated liposarcoma. For dedifferentiated liposarcoma, R₀ resection should be achieved. Radiotherapy is the best treatment for myxoid/round cell liposarcoma, and it is also an important supplement to the treatment of dedifferentiated liposarcoma. In well-differentiated and dedifferentiated pathological types, chemotherapy will increase the risk of death.