Although non-functional islet cell tumor (NFICT) and solid and papillary neoplasm (SPN) share similar clinical and pathological features, the outcome of each is different. Because NFICT often follow a malignant course and SPN are usually benign, the correct differential diagnosis is very important. We investigated the clinical and pathological findings in 10 cases of NFICT and 12 cases of SPN, including immunohistochemical analysis for chromogranin, vimentin, neuron-specific enolase, somatostatin, alpha-1-antitrypsin, estrogen receptor, progesterone receptor, CD99, p21 and Ki-67. The current study shows that chromogranin is the most valuable marker in differentiating between the tumors (P < 0.01). In contrast to previous reports stating that SPN express the progesterone and/or estrogen receptors, which are absent in other pancreatic tumors, our results show that one-third of SPN were positive for the progesterone receptor. Downregulation of p21 was found more frequently in NFICT (40%) than SPN (17%). The mean value of the Ki-67 proliferation index for NFICT (2.77% +/- 2.53%) was significantly higher than that for SPN (0.94% +/- 0.89%; P = 0.043). These results are consistent with NFICT having more malignant behavior than SPN.