Various regimens including molecular targeted agents have been examined in patients with cisplatin (CDDP)-resistant urothelial cancer (UC). However, some studies have been stopped owing to the development of severe adverse events. The main aim of this study was to examine the anticancer effects, changes in the quality of life (QoL), and safety of combined therapy of low-dose gemcitabine, paclitaxel, and sorafenib (LD-GPS) in patients with CDDP-resistant UC. Twenty patients were treated with gemcitabine (700 mg/m(2) on day 1), paclitaxel (70 mg/m(2) on day 1), and sorafenib (400 mg/day on days 8-22). QoL and pain relief were evaluated using the short-form survey (SF)-36 for bodily pain and the visual analog scale (VAS). VAS scores were significantly decreased by both the second- and third-line therapies (P = 0.012 and 0.028, respectively). The bodily pain score from the SF-36 survey was also significantly (P = 0.012) decreased. Complete responses, partial responses, and stable disease were found in 0 (0.0 %), 1 (5.0 %), and 13 patients (65 %), respectively. The median (interquartile range) period of overall survival after starting of this therapy was 7 (5-11) months. Three patients (15.0 %) stopped therapy because of grade 3 fatigue and hand-foot reactions. LD-GPS therapy was well tolerated by patients with CDDP-resistant UC. QoL was maintained, and improvements in their pain levels were found after treatment; pain relief was detected after third-line therapy. We suggest that this treatment regimen is worthy of consideration as second- and third-line therapy for patients with CDDP-resistant UC.