The purpose of this study was to investigate the clinicopathological features and the expression of proteins involved in cell proliferation and the different pathways of apoptosis in retinoblastoma. Nineteen retinoblastoma patients were included, and mitotic index (MI) and apoptotic index (AI) were assessed. The expression of MIB-1, p53, caspase-3, Bcl-2, and Fas protein was assessed by immunohistochemistry. Mann-Whitney U test and Fisher's exact test were used for statistical comparison. High MI (mean 16.84, range 0-66) and high MIB-1 expression (mean 57.89, range 0-90) were found. The MI was significantly related to MIB-1 expression (P = 0.01). The tumors showed a high apoptotic index (mean 40.26, range 1-110), and the AI was associated with the mitotic index (P = 0.02). The caspase-3 expression was positively related to the AI (P = 0.03), although a small number of tumors with no significant or very low caspase-3 staining showed a high number of apoptotic cells, suggestive of a caspase-3-independent apoptosis pathway. Bcl-2 expression was not significantly related to AI (P = 0.07). No striking relationship was found in expression patterns of p53, Bcl-2, caspase-3, and Fas. In conclusion, we found that (1) cell proliferation and apoptosis are linked in retinoblastoma; (2) activation of effector caspase-3 induces apoptosis in retinoblastoma, but Bcl-2 overexpression does not prevent apoptosis in many tumors; (3) there is a p53-independent pathway in approximately one-quarter of cases; (4) the findings suggesting a caspase-3-independent pathway might lead to apoptosis in retinoblastoma; and, finally, we found no consistent pattern of expression of apoptotic and antiapoptotic molecules, suggesting that in retinoblastoma there is no preference for any single pathway of apoptosis. Confirmation of the results in a large set of tumors would be useful.