Randomized trials support the use of neoadjuvant chemotherapy in muscle-invasive bladder cancer based on a noted survival advantage, which appeared to be strongly related to downstaging of the cancer to pT0 (complete pathologic response). This report presents a case of an unusual mast cell response along with bladder wall thickening after neoadjuvant chemotherapy. However, the final cystectomy specimen did not reveal any residual tumor (pT0). The authors hypothesize that neoadjuvant chemotherapy could have caused the diffuse mast cell response, and that this profound inflammatory response can be used as a biomarker of complete response to chemotherapy.