The relevance of PD-L1 expression on tumor cells (TC) in clear cell renal cell carcinoma (ccRCC) is debatable. However, it is known to be related to responsiveness to anti-PD-1-based therapy in some tumor forms. Using tumor heterogeneity as a guide, researchers identified molecular correlates of TC PD-L1 expression in ccRCC and evaluated their function in predicting response to anti-PD-1 monotherapy. Transcriptomic characteristics associated with PD-L1 status were found using RNA sequencing of matched TC PD-L1 positive and negative regions isolated from 8 ccRCC tumors. Confirmation and correlation of transcriptome profiles with clinical outcomes were performed using a cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) experiment. Overexpression of immune- and cell proliferation-related pathways, upregulation of T-cell activation markers, and higher tumor-infiltrating immune cells were all correlated with TC PD-L1 expression, both in the matched samples and the CM-025 cohort. There was no correlation between TC PD-L1 expression and health outcomes in the CM-025 cohort. Longer PFS (HR, 0.32; 95% CI, 0.13-0.83) and higher objective response rate (30% vs. 0%, P=0.04) on nivolumab compared with everolimus were seen in a molecular RCC subtype characterized by combined overexpression of immune- and cell proliferation-related pathways (previously defined by unsupervised clustering of transcriptomic data). In ccRCC, the control of TC PD-L1 expression is believed to be a collaborative effort between TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation-related) mechanisms. In ccRCC, TC PD-L1 expression alone may not be the best predictor of response to anti-PD-1-based therapy, but the quantification of these transcriptional programs may be.