Bacillus Calmette-Guerin (BCG) is currently employed in the treatment of superficial bladder cancer but, despite its recognized effectiveness in preventing recurrences and progression, the immune mechanisms behind its antitumor activity remain to be delineated. In this study we provide evidence that a prolonged increase in the plasma levels of IL-2, but not IL-1beta, IL-4, IL-10, IL-2R or TNF-alpha occured in patients affected by bladder cancer following effective BCG treatment. Conversely, a drop in circulating IL-2 was consistently associated with tumor relapse. The level of IL-2 was elevated even further 15 days after the last BCG administration in patients who did not experience tumor recurrence, suggesting a prolonged T cell-mediated response against antigens other than BCG. Our results indicate that a specific type 1 immune response plays a major role in the anti-cancer activity of BCG. In addition, monitoring IL-2 plasma levels may offer a useful tool for predicting tumor recurrences.