This study was performed to identify differences in gene expression between superficial noninvasive and invasive transitional cell carcinoma (TCC) of the bladder in human beings. We used complementary deoxyribonucleic acid microarrays containing 14,551 different genes to analyze gene expression among 6 cases of superficial and 6 cases of invasive TCC of the bladder to identify differences in gene expression, which might explain differences in the biology and clinical outcomes of these histologic subtypes of TCC. Quantitative real-time polymerase chain reaction was performed for selected genes to validate the microarray data. Significant up-regulation of 40 genes was associated with cases of superficial noninvasive, but not in invasive, TCC of the urinary bladder. This effect included genes involved in epithelial cell dedifferentiation and keratinization, as well as genes related to cell cycle, cell adhesion, transcription, and apoptosis. Conversely, significant up-regulation of 34 genes was associated with cases of invasive TCC, but not in superficial TCC, including genes related to extracellular matrix degradation, immune responses, cell cycling, and angiogenesis. This study shows the usefulness of complementary deoxyribonucleic acid microarray technology for identifying differences in gene expression among different histotypes of bladder cancer.