Background and Aims Distal cholangiocarcinoma (DCC) is characterized by insidious onset, high degree of malignancy, and difficult early diagnosis. Most patients have progressed to the middle or late stage at the time of diagnosis, with no chance for radical treatment. So, identifying reliable serum markers of DCC is of great importance for early diagnosis and treatment benefit assessment. The systemic immune-inflammatory index (SII) calculated by lymphocyte, neutrophil and platelet and counts is a comprehensive inflammatory index, and has been used for prognostic analysis in variety of malignant conditions. However, its application value in DCC patients has not been demonstrated. Therefore, this study was conducted to investigate the prognostic value of SII in DCC patients after pancreatoduodenectomy (PD).Methods The clinical data of 117 DCC patients undergoing PD in Fuxin Mining General Hospital of Liaoning Health Industry Group from January 2010 to June 2016 were retrospectively analyzed. Using the ROC curve approach, the performances of preoperative SII, platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in predicting the 5-year overall survival (OS) of DCC patients were rated, and the optimal cut-off vale of SII to evaluate the prognosis of DCC patients was determined. The relations of SII with the clinicopathologic characteristics of the patients were analyzed, and the risk factors for postoperative survival of the patients were determined by univariate and multivariate analyses.Results The prediction efficiency of preoperative SII (AUC=0.649) was higher than that either of PLR (AUC=0.595) or NLR (AUC=0.552), and its cut-off value was 975. In high SII group (SII>975), the proportions of patients with preoperative cholangitis, high levels of CEA and CA19-9 and large intraoperative blood loss were higher than those in the low SII group (SII≤975), with statistical significance (all P<0.05), while there were no significant differences in recurrence rate, recurrence site and other clinicopathologic variables between the two groups (all P>0.05). The median survival time for the entire group was 49 (19-104) months. Univariate analysis showed that preoperative CA19-9 level, vascular invasion, lymph node metastasis, T stage, portal vein reconstruction, degree of radical resection, and preoperative SII were significantly associated with the postoperative 5-year OS of DCC patients (all P<0.05). Multivariate analysis revealed that the presence of lymph node metastasis (HR=2.406, 95% CI=1.437-4.026, P=0.001), portal vein reconstruction (HR=1.549, 95% CI=1.075-2.365, P=0.043), and SII>975 (HR=1.793, 95% CI=1.205-2.668, P=0.015) were independent risk factors for postoperative 5-year OS of DCC patients.Conclusion Preoperative SII is an effective indicator for predicting the postoperative prognosis in DCC patients. DCC patients with SII>975 may face a poor postoperative prognosis, and for them the follow-up should be strengthened and other treatment measures should be considered.