Objective: To evaluate the prevalence of malignancies in a multicenter cohort of Chinese patients with immunoglobulin G4-related disease (IgG4-RD) and to identify the related risk factors of malignancy in IgG4-RD patients. Methods: We retrospectively analyzed 602 IgG4-RD patients who were recruited in 5 medical centers from 2009 to 2020. Standardized prevalence ratios (SPRs) against general Chinese population were calculated along with 95% confidence intervals (CIs). We identified the risk factors of malignancy in IgG4-RD and calculated the odds ratios (ORs) of different factors. Then, we developed and validated a prediction model for malignancy risk of IgG4-RD based on our cohort. Results: We observed a significantly increased prevalence of total malignancies in this cohort compared to general Chinese population (SPR 8.66 [95%CI 5.84, 12.31]). Logistic regression analysis indicated that eosinophil percentage (OR 1.096 [95%CI 1.019-1.179], P=0.016), serum albumin to globulin ratio (AGR) (OR 0.185 [95%CI 0.061-0.567], P=0.002) and autoimmune pancreatitis (OR 2.400 [95%CI 1.038-5.549], P=0.041) were three independent risk factors of malignancy in IgG4-RD patients. Four predictors were included in our final prediction model: age at IgG4-RD diagnosis, eosinophil percentage, AGR and autoimmune pancreatitis. The nomogram performed well in the internal validation cohort, with a concordance index (C-index) of 0.738.Conclusion: A significantly increased prevalence of total malignancies were observed in our multicenter cohort. Eosinophil percentage and autoimmune pancreatitis are risk factors, whereas AGR is negatively associated with malignancy in IgG4-RD. A prediction model for malignancy risk of IgG4-RD was first developed and validated in our study.