For many malignancies, considerable divergence between the efficacy found in clinical trials and effectiveness in routine practice have been reported (efficacy-effectiveness gap). The purpose of this study was to evaluate the efficacy-effectiveness gap in palliative first-line (1L) chemotherapy treatment (CTx) for urothelial carcinoma of the bladder. From seven Dutch teaching hospitals, all patients diagnosed with unresectable stage III (cT2-4aN1-3M0) and IV (cT4b and/or cM1) disease, who received 1L-CTx (for both primary as recurrent disease after radical cystectomy) between 2008 and 2016, were captured. Results were compared with data from seven randomised trials that investigated 1L gemcitabine + cisplatin (GemCis) and/or gemcitabine + carboplatin (GemCarbo). Of the 835 included patients, 191 received 1L-CTx. Median overall survival (mOS) of GemCis patients (N = 88) was 10.4months [95% CI 7.9-13.0], which was shorter compared to clinical trial findings (range mOS: 12.7-14.3months) despite comparable clinical characteristics. The mOS of GemCarbo patients (N = 92) was 9.3months [95% CI 7.5-11.1]. Patients who received GemCarbo had worse prognostic characteristics (higher age, impaired renal function and worse performance status (all P-values < 0.001)) compared to GemCis patients, but were equal in occurrence of dose reductions (24.4% vs. 29.5%, P-value = 0.453), early termination (55.7% vs. 54.1%, P-value = 0.839), clinical best response (P-value = 0.733), and toxicity (68.1% vs. 63.3%, P-value = 0.743). In multivariable regression, GemCis was not superior to GemCarbo (HR 0.90 [95% CI 0.55-1.47], P-value = 0.674). There seems to be an efficacy-effectiveness gap in 1L GemCis treatment, despite patients having similar baseline characteristics. Early termination of treatment occurred more often and dose reduction less often compared to clinical trials, hinting towards abandonment of treatment in case of adverse events. Patients treated with 1L GemCis did not have superior survival compared to GemCarbo patients, even though GemCarbo patients had worse baseline characteristics.