Enfortumab vedotin (EV), a nectin-4-directed antibody conjugated to monomethyl auristatin E (MMAE), has been approved for patients with advanced urothelial carcinoma (aUC) previously treated with platinum-based chemotherapy and immune inhibitors. Taxane agents and MMAE share antitumor mechanisms through microtubule disruption, thus raising a notable concern regarding cross-resistance between these drugs. This case report describes two patients with taxane-based chemotherapy-refractory aUC who responded well to EV. A 71-year-old man (case 1) with pT3N0M0 renal pelvic UC showed a partial response to EV in metastatic lesions of the bilateral lungs and right pelvic lymph nodes after three cycles of paclitaxel plus gemcitabine chemotherapy. A 53-year-old man (case 2) with cT3bN2M0 bladder UC underwent platinum-based neoadjuvant chemotherapy and the following radial cystectomy (ypTis ypN0). He developed bilateral lung metastases and showed a complete response to EV in the metastatic lesions after 20 cycles of paclitaxel plus nedaplatin chemotherapy. Our experience of two cases demonstrated that tumor response to EV can be expected in patients with taxane-refractory aUC.