Background: Predictive markers are needed for improved selection of patients for Capecitabine/Temozolomide (C/T) therapy in metastatic PanNETs. Treatment efficacy has been reported to correlate with tumor O6-methylguanine-methyltransferase (MGMT) deficiency. Based on these data, retained MGMT expression by IHC has been proposed as an exclusionary marker. However, a marker would only be clinically useful if it is able to identify patients so unlikely to benefit that treatment would be inappropriate. We conducted a retrospective analysis to assess MGMT expression in PanNETs and to correlate this with the efficacy of C/T. Methods: Using an institutional electronic pharmacy database, we identified patients with PanNETs with tissue available treated with C/T from 1/2003-10/2013. Expression of MGMT protein was assessed by IHC on primary tumors or metastases. Immunolabeling in ≥5% of tumor nuclei was defined as “positive” staining (retained expression) of MGMT protein. When possible, pyrosequencing to detect the level of methylation in 5 CpG sites in exon 1 of the MGMT gene, was used to evaluate MGMT promoter hypermethylation in the tumor. Results: Thirteen patients (mean age, 57) were identified; 3 (23%) low grade, 8 (61%) intermediate grade, 2 (15%) high grade. 4/13 (31%) patients with evidence of tumor shrinkage had MGMT IHC positive tumors. Of these, 1 patient (promoter hypermethylation absent) had unresectable disease rendered resectable after a significant response to C/T and is now 2 years free of disease. Tissue was unavailable to test for promoter hypermethylation in the remaining 3 patients. Of the 9 patients where MGMT by IHC was absent, all 9 had evidence of tumor shrinkage (100%). Tumor burden (0%, <10%, 10-50%, >50%), number of prior systemic treatments, and tumor grade did not correlate with tumor shrinkage. Conclusions: In this study, absence of MGMT expression correlated with response, however 30% of MGMT positive tumors responded. More discriminant markers are required. The possibility that hypermethylation of MGMT gene is a predictor is being explored in ongoing studies.