Background: The ULISSE registry evaluated the real-world performance of the Ultimaster® biodegradable polymer sirolimus-eluting stent (BP-SES) in a multicenter-independent cohort of patients undergoing percutaneous coronary intervention, including a large proportion of diabetes mellitus (DM) patients. Methods: In this subgroup analysis, 1,660 consecutive patients, 2,422 lesions, treated with BP-SES enrolled in the ULISSE registry were divided in two groups: DM (485 patients, 728 lesions) and non-DM (1,175 patients, 1,694 lesions). Primary endpoint was target lesion failure (TLF), a composite endpoint of cardiac-death, target-vessel myocardial infarction (TV-MI), and clinically driven target lesion revascularization (TLR) at 1-year. Secondary endpoint was TLR at 1-year. Results: At 1-year follow-up TLF occurred in 5% overall patients and was significantly higher in DM patients (8 vs. 3.7%; p =.001), due to more cardiac deaths (3.4 vs. 1.1%; p =.002). TLR occurred in 3.2% overall patients, and it was not significantly higher in DM compared to non-DM patients (4.4 vs. 2.8%; p =.114). The incidence of stent thrombosis was low and similar between groups (0.4 vs. 0.9%; p =.526). Insulin-treated DM (ITDM) patients showed higher rate of TLF as compared to non-ITDM patients (13 vs. 6.5%; p =.041), but similar rate of TLR (6 vs. 4%; p =.405). After adjustment for relevant comorbidities, DM was not significantly associated with TLF or cardiac death in patients undergoing BP-SES implantation. Conclusions: This study is the first all-comers evaluation of BP-SES in DM patients. Our findings show that DM patients, mostly those with ITDM, still represent a vulnerable population and experience significantly higher rate of TLF. Overall BP-SES efficacy is considerable, although not statistically significant higher rate of TLR is still present in DM compared to non-DM patients.