Background and Aims In recent years, the clinical value of perineural invasion for prognosis assessment and treatment decision support in patients with intrahepatic cholangiocarcinoma (ICC) has been increasingly recognized. There is growing evidence that adjuvant chemotherapy can improve the prognosis of ICC patients. However, there remains some controversy regarding whether adjuvant chemotherapy can effectively improve the overall survival (OS) of ICC patients with perineural invasion. Therefore, this study was performed to explore the risk factors for perineural invasion in ICC and analyze the efficacy of adjuvant chemotherapy for patients with concurrent perineural invasion, so as to provide support for clinical decision-making.Methods The clinicopathologic data of 259 patients who underwent curative-intent resection for ICC in the Department of Hepatobiliary Surgery of the First Affiliated Hospital of Xi'an Jiaotong University from January 2013 to December 2022 were retrospectively collected. The risk factors for perineural invasion in ICC patients, factors influencing postoperative prognosis of patients, and the impact of adjuvant chemotherapy on prognosis were analyzed.Results Among the 259 patients, 17.7% (46/259) had concomitant perineural invasion. The median OS time for patients without perineural invasion was 25.0 months, with 1-, 3-, and 5-year overall survival rates of 71.3%, 38.2%, and 26.6%, respectively. For patients with perineural invasion, the median OS time was 10.0 months, with 1-, 3-, and 5-year overall survival rates of 39.1%, 21.4%, and 0.0%, respectively. The difference in survival rates between the two groups was statistically significant (χ²=8.400, P=0.004). The preoperative total bilirubin level, CEA level, CA19-9 level, viral hepatitis, intrahepatic stones, liver function Child-Pugh classification, tumor location, tumor size, vascular invasion, N stage, and TNM stage were significantly associated with perineural invasion in ICC (all P<0.05). CA19-9 level (OR=2.265, 95% CI=1.061-4.833), intrahepatic stones (OR=4.064, 95% CI=1.809-9.130), vascular invasion (OR=3.286, 95% CI=1.551-6.964), and N stage (OR=2.365, 95% CI=1.149-4.869) were independent risk factors for perineural invasion in ICC (all P<0.05). Prognostic analysis showed that CA19-9 level (HR=1.615, 95% CI=1.142-2.283), intrahepatic bile duct stones (HR=2.093, 95% CI=1.401-3.127), vascular invasion (HR=1.563, 95% CI=1.032-2.367), perineural invasion (HR=2.120, 95% CI=1.392-3.229), and N stage (HR=2.304, 95% CI=1.320-4.022) were independent risk factors for OS after curative-intent resection for ICC (all P<0.05), while adjuvant chemotherapy was an independent protective factor for overall survival after ICC surgery (HR=0.533, 95% CI=0.369-0.770, P<0.05). Further analysis showed that adjuvant chemotherapy could effectively prolong the median OS time in both the entire group of ICC patients and those with perineural invasion (both P<0.05), but its effect on prolonging median OS time in ICC patients without perineural invasion was not significant (P>0.05).Conclusion CA19-9 level, intrahepatic stones, vascular invasion, and N stage are closely related to perineural invasion in ICC. Patients with concomitant perineural invasion have poorer postoperative prognosis, but adjuvant chemotherapy can effectively improve the prognosis of such ICC patients.