The p16-cyclin D-Cdk4(6)-pRB-E2F and p73 pathways are involved in the control of cell-cycle progression, and genetic lesions in both pathways frequently occur in breast carcinomas and other human cancers. The p16INK4a gene is involved in regulation of the G1/S transition, and when overexpressed, the p73 gene activates transcription of p53-responsive genes and promotes apoptosis. These pathways are related, for instance, p73 is also downstream of E2F-1, since E2F-1 induces p73-mediated apoptosis in the absence of p53. We studied 93 breast cancer patients to identify alterations in the expression of p16INK4a and p73 by semiquantitative RT-PCR analysis and possible interactions between them and correlations with clinicopathological parameters. p73 was overexpressed in 24 cases. Overexpression of p16INK4a was detected in 17 cases and underexpression in 32 cases. A significant correlation was observed between the overexpression of both genes (P = 0.05). Concurrent overexpression of p73 and p16INK4a was significantly correlated with metastases in three or more lymph nodes (P = 0.0007), positive immunohistochemistry for p53 (P = 0.014), vascular invasion (P = 0.048) and negative progesterone receptors (P = 0.004). These results indicate that concomitant overexpression of p16INK4a and p73 may be involved in breast cancer and associated with poor tumor characteristics.