Introduction: To measure the level of endothelial cell-specific molecule-1 (ESM-1) expression among the Renal Cell Cancer (RCC) variants using by immunohistochemical method and determine the relationship between ESM-1 expression and RCC prognosis. Materials and Methods: ESM-1 immunoreactivity scores (IR) were measured in appropriate renal tumoral tissue blocks of 153 consecutive RCC patients in this retrospective analysis of prospectively collected data. Mean ESM-1 IR scores were calculated in patients who were pathologically diagnosed with clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). Progression-free survival and overall survival were evaluated using the log-rank test according to ESM-1 IR scores. Survival rates were calculated using Kaplan-Meier survival analysis. Results: In the ccRCC group, the mean ESM-1 IR scores of those with local invasion were significantly higher than those without local invasion (P = 0.014). The mean ESM-1 IR score of patients with metastatic ccRCC was significantly higher than those with non-metastatic ccRCC (P < 0.001). Considering all patients regardless of RCC subtype pathologies, the mean ESM-1 IR score in clinical stage 1 tumor was 3.82 ± 1.98, 4.87 ± 1.74 in clinical stage 2, 5.88 ± 2 in clinical stage 3, and 6.60 ± 2.23 in clinical stage 4. The mean ESM-1 IR score of patients with metastatic ccRCC was significantly higher than those with non-metastatic ccRCC (P < 0.001). The mean follow-up period for all patients in this study was 71 months (range 1–120 months). It has been shown that the higher the ESM-1 IR score, the lower the 10-year overall survival and disease-free survival rates (P = 0.026, P = 0.005). Conclusion: Immunohistochemical expression of ESM-1 may be a promising prognostic biomarker in RCC. Currently, some prognostic scoring systems are available for patients with localized and metastasized RCC. Incorporating ESM-1 expression in RCC into these existing prognostic scoring systems could improve these models and enhance the quality of individual oncologic management in RCC patients.