Rhabdoid differentiation has been associated with aggressive behavior in carcinomas from different organ systems. A recent consensus statement of the International Society of Urological Pathology (ISUP), in addition to proposing a nucleolar grading system (ISUP grade) for renal cell carcinoma (RCC) to replace the Fuhrman system, recommended reporting the presence of rhabdoid differentiation in RCC and considering tumors with rhabdoid differentiation to be ISUP grade 4. Although it has been shown that rhabdoid differentiation is associated with increased grade and stage of RCC, it has not been fully demonstrated whether it has an adverse effect independent of this association with increased grade and stage. We provide the largest clinicopathologic analysis of RCC with rhabdoid differentiation to date (76 cases), including characterization of metastatic disease. In addition, by constructing a multivariable model including tumor grade, stage, necrosis, and distant metastasis to compare a series of 49 clear cell RCC with rhabdoid differentiation with a cohort of 41 clear cell RCCs without rhabdoid differentiation, we demonstrate that the presence of rhabdoid differentiation in clear cell RCC confers an increased risk of death (hazard ratio=5.25; 95% confidence interval, 2.1-14.3) independent of these other adverse prognostic factors. These findings underscore the significance of rhabdoid differentiation in RCC as an adverse prognostic factor and support the recent reporting and grading recommendations of the ISUP. © 2014 by Lippincott Williams and Wilkins.