Endothelin-1 (ET-1) is a multifunctional peptide exerting its effects via receptors A and B. ET-1 and its receptors, endothelin axis (ET axis), play a promoting role in cancer biology. Alterations of proteins of ET axis have been detected in non-metastatic muscle-invasive bladder cancer (NMMIBC). The objective of this study is to investigate the potential role of ET-1 tumor expression as a biomarker of prognosis, compared to other prognostic parameters (epidemiologic and pathologic), in NMMIBC. We prospectively included 40 consecutive, primary, high-grade NMMIBC patients. Tumor specimens after initial transurethral resection were stained immunohistochemically for ET-1. The ET-1 evaluation of expression was based on staining intensity (SI) of ET-1. SI was classified according to an arbitrary four-tiered scale (negative = 0, mild = 1, moderate = 2, strong = 3). Epidemiologic and pathologic parameters were analyzed, using univariate and multivariate statistics, for disease progression, progression-free survival (PFS), and overall survival (OS). ET-1 overexpression (SI = 3) was the unique parameter which associated significantly, both in univariate (log-rank test, p = 0.033) and multivariate (Cox regression analysis, p = 0.045, HR = 4.849, 95 % CI: 1.039-22.624) analysis, with an increased hazard ratio of progression. ET-1 overexpression (SI = 3) was also the unique parameter which associated, marginally significantly in univariate analysis (log-rank test, p = 0.056) and highly significantly in multivariate analysis (Cox regression analysis, p = 0.005, HR = 7.001, 95 % CI: 1.782-27.501), with an increased hazard ratio of death. Overexpression of ET-1 may be a potential biomarker of unfavorable prognosis in NMMIBC patients.