Background: Temozolomide (TMZ) is an alkylating agent that has shown good results in the treatment of neuroendocrine and central nervous system (CNS) tumors. The loss of O-6-methylguanine-DNA methyltransferase (MGMT) expression by pyrosequencing (PSQ) is a predictive factor of response to treatment with TMZ in high-grade gliomas. However, its predictive value in pancreatic neuroendocrine tumors (pNET) is controversial, and there is no consensus on how to best assess MGMT. The aim was to evaluate the objective response rate in pNET according to the state of MGMT, assessed by PSQ for evaluation of promoter methylation and immunohistochemistry (IHC). Methods: Patients with pNET who were treated with TMZ at the center between 2008 and 2017 were studied retrospectively. Ten patients were included in the study. A deficiency of MGMT was determined by IHC and MGMT promoter methylation by PSQ. For IHC, the cut-off was 10%, defined as negative < 10% of tumor cells positive in the tumor tissue. For the PSQ, the cut-off was 8%, defined as methylated who presented > 8%. Results: A deficiency of MGMT was detected in five patients (50%) by IHC. An MGMT promoter methylation by PSQ was observed in three patients (30%). The IHC results were consistent with PSQ results in only six patients (60%); one patient with methylated MGMT had positive IHC, and three patients had unmethylated MGMT by PSQ unmethylated, IHC negative. PSQ had a high positive predictive value of response because the three patients with MGMT promoter methylation by PSQ presented objective responses (OR). Nevertheless, a low negative predictive power (57%) was observed because three of seven patients with unmethylated MGMT presented OR. Of the five patients with MGMT deficiency by IHC, four (80%) presented OR, suggesting positive predictive value of 80%; however, it also presented a low negative predictive power of 60%. Conclusions: Despite having 100% of the patients with MGMT promoter methylation showing OR in this series, the low negative predictive power suggests that the absence of MGMT deficiency by IHC or MGMT unmethylated by PSQ does not contraindicate the use of TMZ in pNET treatment.