Abstract Background/Purpose: O6-methylguanine-DNA methyltransferase (MGMT) has been linked with alkylating agent resistance and tumor growth suppression. However, its role remains undetermined in pancreatic neuroendocrine neoplasms (Pan-NENs). This study examined the expression of MGMT in Pan-NENs and explored how MGMT affects the efficacy of the alkylating agent streptozocin (STZ). Methods: The expression of MGMT was examined by immunohistochemistry (IHC) staining in 146 Pan-NEN patients at our institute; MGMT immunoreactivity and clinicopathological factors were evaluated. Results: In 146 Pan-NEN, 99 cases (67.8%) were judged as MGMT-positive and 47 cases (32.2%) as negative. MGMT-negative cases were associated significantly with larger tumor size (p<0.001), higher mitotic index (p<0.001), and higher Ki-67 index (p<0.001). Of the 19 cases treated with STZ, 6 cases were determined as SD and 4 cases as PD in MGMT-positive patients (N=10), while 5 cases were determined as PR and 4 cases as SD in MGMT-negative patients (N=9). Progression-free survival in MGMT-negative cases was significantly better than in MGMT-positive cases (p=0.042). Conclusions: MGMT expression was decreased with higher grade Pan-NENs, and STZ improved the therapeutic outcomes of MGMT-negative Pan-NENs. These findings indicate that higher grade Pan-NENs may represent a better therapeutic target for STZ treatment.