Bacillus Calmette Guerin (BCG) is generally regarded as an effective immunotherapy for superficially invasive papillary transitional cell carcinoma of the bladder. The exact mechanism(s) which underlie its efficacy are unknown. As C-erbB-2 oncoprotein and vascular endothelial growth factor (VEGF) have been shown to be over-expressed in TCC of the bladder, it has been postulated that they may be important in its pathogenesis. The purpose of this study was to 1.) differentially evaluate the effect of BCG immunotherapy in treated and untreated cohorts on the immunohistochemical expression of C-erbB-2 and VEGF in formalin-fixed paraffin-embedded sections of superficial and superficially invasive (Stage Ta-T1) transitional cell carcinoma of the bladder. Immunolabeling intensity was assessed independently by two pathologists and reported as a mean labeling index. The results confirm previous studies that 1.) both c-erbB-2 and VEGF are over-expressed in these tumors MLI = 90.1 and 45.7 respectively, 2.) that VEGF is an early and sensitive indicator of TCC, and 3.) that BCG has a salutary effect on papillary TCC, 66% vs. 89% recurrence rate, P = .04. Our findings show that 1.) C-erbB-2 expression is decreased in patients tumors which show response to BCG (45.7 to 38.5), P = 0.15, 2.) that BCG administration has no effect on the expression of VEGF. While the decrement in c-erbB-2 immunostaining observed in those patients who received BCG contrasts with the increase in c-erbB-2 immunolabeling observed in patients who did not receive BCG, the differences were not statistically significant and could reflect tumor grade or stage regression associated with BCG therapy. However, this study suggests that BCG differentially influences the expression of C-erbB-2 and VEGF.