BACKGROUND: Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first‐line palliative chemotherapy. There are, however, no published studies concerning second‐line treatment of the disease. Temozolomide has shown clinical effect in well‐differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first‐line treatment. METHODS: Twenty‐five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively. RESULTS: One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression‐free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation. CONCLUSIONS: Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first‐line chemotherapy. These results indicated that temozolomide may be used as second‐line treatment in PDEC. Cancer 2011;. © 2011 American Cancer Society. In poorly differentiated endocrine carcinoma, treatment with temozolomide had good effect and was well tolerated as second‐line treatment.