Objective: To identify morbidity and mortality risk factors in patients with synchronous diseases who underwent single-stage combined (SSC) surgery. Methods: We considered data of 328 patients, each with multiple, elective, synchronous surgical problems treated by a SSC operation. By univariate and multivariate analysis we evaluated many patient-, disease - or treatment-related variables with respect to post-operative mortality, morbidity, and hospital stay. Results: Two combined procedures were synchronously performed in 283 patients (86%), 3 combined procedures in 45 patients (14%). Post-operative mortality and morbidity rates were 3% and 24%, respectively, and median duration of hospital stay was 9 days. The occurrence of a surgical oncology procedure emerged as the most important independent risk factor for post-operative mortality and morbidity. Conclusions: The safety of SSC surgery for the treatment of synchronous problems appears similar to that of multi-stage procedures. The understanding of risk factors for this surgical approach could be useful in order to improve patient selection.