Intravesical adjuvant chemotherapy and neoadjuvant chemotherapy has been respectively administered for superficial transitional cell carcinoma (TCC) of urinary bladder and advanced TCC for years. However, the therapeutic efficacy is limited. Recently, overexpression of aldo-keto reductase (AKR) in lung, esophageal, uterine cervical and ovarian cancers was shown to be closely associated with disease progression and drug resistance. In this study, we used immunohistochemistry to determine AKR expression in pathological specimens of 347 patients with urinary bladder cancer (UBC). Some of these patients were from areas with a high risk of black foot disease (BFD), a disease that is closely associated with arsenic contamination of drinking water. The presence of AKR was confirmed by immunoblotting, matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF) and reverse transcription-polymerase chain reaction (RT-PCR). AKR isotype was determined by cDNA sequencing. Our results showed overexpression of AKR1C2 in 226 (65.1%) patients. BFD areas had a higher frequency of patients expressing AKR1C2 in UBC. Among AKR1C2-positive UBC, 148 (65.5%) were invasive, 70 (31.0%) were non-invasive and 8 (3.5%) were carcinoma in situ (CIS). These data indicated that AKR1C2 expression could be significantly associated with cancer invasiveness (p<0.001) and disease progression. Because BFD has been closely related to arsenic ingestion, our results suggested that continual intake of arsenic in drinking water might provoke AKR1C2 expression that could in turn induce drug resistance in UBC, and AKR1C2 could be a tumor marker for UBC.