Abstract Objectives. To investigate the incidence of baseline apoptosis in relation to p27 Kip1, p53, and p21 Cip1 expression, proliferation status, standard clinicopathologic parameters, and patient outcome. Cell cycle regulators and apoptotic cell death have been implicated in tumor aggressiveness in many human malignancies. Their interaction, however, in the prognosis of patients with transitional cell carcinoma (TCC) of the urinary bladder has not yet received intense scrutiny. Methods. Apoptotic fractions were quantified immunohistochemically by means of a novel monoclonal antibody recognizing single-stranded DNA regions in apoptotic nuclei in 103 paraffin-embedded primary TCC specimens. Proliferative activity was expressed as the percentage of Ki-67 positive cells (Ki-67 index). Tissue specimens were also stained for p27 Kip1, p53, and p21 Cip1 proteins. Patients were followed up until death (n = 30) or for an average of 40 months (median 36). Results. The apoptotic index increased with grade, T stage, nonpapillary status, proliferative activity, and p53 expression and was inversely related to p27 Kip1 and independently to p21 Cip1 expression. A negative correlation was found between p27 Kip1 expression and proliferation. The increased apoptotic index had an adverse impact on overall and disease-free survival (univariate analysis) and, along with T stage, was an independent predictor in muscle-invasive TCC. Conclusions. An increased apoptotic rate, increased proliferative activity, and decreased p21 Cip1 expression are independently interrelated in TCC. More importantly, the assessment of apoptotic potential appears to be more informative than standard prognosticators in predicting overall survival in patients with muscle-invasive TCC.