Background: Capecitabine and temozolomide are active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30% to 70%. Several small retrospective series have suggested that MGMT deficiency may predict response to temozolomide, however expression of MGMT has not been validated as a predictive biomarker. Cytotoxic chemotherapy is thought to be most active in aggressive tumors, however the ki-67 index has not been formally evaluated as a predictive factor. It is unclear whether chromosomal instability (which correlates with alternate lengthening of telomeres) predicts response. Methods: 144 patients with pNET who underwent treatment with capecitabine/temozolomide were retrospectively evaluated for radiographic response. The predictive role of ki-67% and MGMT by immunoistochemestry as well as ALT activation by FISH was assessed on up to 59 evaluable archival specimens. Frequently altered genes in pNETs were also sequenced and their status was correlated to the radiographic response. Results: The ORR was 63%. Response to treatment was significantly higher in tumors with ki-67 > 5% (n = 28) as compared to tumors with ki-67 ≤ 5% (n = 31) (ORR: 64% vs 29%; p = 0.006). MGMT status (p = 0.358) and ALT pathway activation (p = 0.174) were not predictive of response. Conclusions: pNETs with ki-67 > 5% are more likely to respond to capecitabine/temozolomide. MGMT status appears to have no correlation with response.