The association between simian virus (SV40) and malignant pleural mesothelioma (MPM) suggests an etiological role for SV40. However, exact pathogenetic mechanisms and possible prognostic value are not clear. The purpose of the present paper was to investigate 40 Egyptian MPM patients for the presence of SV40 DNA, altered Rb expression and p53 gene status using immunohistochemistry and molecular techniques. The relation between SV40, asbestos exposure, Rb, p53 and their contribution to the overall survival (OS) were also assessed. SV40 DNA was detected in 20/40 patients and asbestos exposure in 31 patients; 18 of them were SV40 positive. Altered p53 and Rb expression were detected in 57.5% and 52.5%, respectively, with no p53 mutation. Univariate analysis showed a significant correlation between OS and stage (P = 0.03), performance status (P = 0.04), p53 overexpression (P = 0.05), asbestos exposure (P = 0.002) and SV40 (P = 0.001). Multivariate analysis showed that when SV40 and asbestos exposure were considered together, only combined positivity of both was an independent prognostic factor affecting the OS (P = 0.001). SV40 and asbestos exposure are common in Egyptian MPM, denoting a possible etiological role and a synergistic effect for both agents. Combined positivity for SV40 and asbestos exposure is an independent prognostic factor in MPM, having a detrimental effect on OS.