In this study, the expression of epidermal growth factor receptor (EGFr) and c-erb-B-2 was evaluated in 35 formalin-fixed, paraffin-embedded cases of transitional cell carcinomas of the urinary bladder (TCCs). EGFr and c-erb-B-2 expression was assessed with immunohistochemistry, and molecular analysis of the respective genes was performed with the differential polymerase chain reaction. The results were statistically analyzed in relationship to histologic grade, stage, and clinical outcome. Strong cytoplasmic expression of the EGFr using the polyclonal antibody Ab-4 was found in three (25%) Grade 2 and eight (67%) Grade 3 TCCs (P < 0.01). Two Grade 2 (17%) and 11 (92%) Grade 3 TCCs strongly expressed the anti-c-erb-B-2 Ab-3 antibody. None of Ta/T1 TCCs cases showed strong expression against EGFr, in contrast to c-erb-B-2 where two cases (18%) were found to express an intense immunosignal. Eleven (85%) T2/T3 cases showed strong positivity either against EGFr or c-erb-B-2 (P < 0.001). Eleven patients died within 12 months after the diagnosis, and all of them showed strong expression of EGFr and c-erb-B-2. Amplification of EGFr and c-erb-B-2 genes was identified in one (3%) and four (11%) TCCs cases, respectively. All patients with amplified genes died within 12 months from the date of diagnosis. Our results indicate that simultaneous expression of EGFr and c-erb-B-2 occurs in TCCs, is related to the histologic grade and the stage of the disease, and denotes aggressive biologic behavior.