Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors. Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O6-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing. From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6-48.7) and 14.7 months (10.1-18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity. This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.