Abstract Background In insulin-treated patients with type 2 diabetes mellitus (T2DM), glycemic control is usually suboptimal. Methods This study compared the risks of mortality and cardiovascular events in insulin-treated patients adding or not adding alpha-glucosidase inhibitors (AGIs). Results This cohort study included data from the Taiwan National Health Insurance Research Database. In total, 17,417 patients newly diagnosed as having T2DM and undergoing insulin therapy during 2000–2012 were enrolled. Overall incidence rates of all-cause mortality, hospitalized coronary artery disease (CAD), stroke, and heart failure were compared between 4165 AGI users and 4165 matched nonusers. The incidence rates of all-cause mortality were 17.10 and 19.61 per 1000 person-years in AGI nonusers and users, respectively. Compared with nonusers, AGI users had a higher mortality risk [adjusted hazard ratio (aHR) = 1.21, 95% confidence interval (CI) = 1.05–1.40; p = 0.01]. Regarding AGI use, aHRs (95% CI) for cardiovascular death, non-cardiovascular death, hospitalized CAD, stroke, and heart failure were 1.20 (0.83–1.74), 1.27 (1.07–1.50), 1.12 (0.95–1.31), 0.98 (0.85–1.14), and 1.03 (0.87–1.22) respectively. Conclusion AGI use was associated with higher risks of all-cause mortality and non-cardiovascular death in insulin-treated patients with T2DM. Therefore, adding AGIs in insulin-treated patients may not be appropriate.