Importance: Therapies to inhibit programmed cell death 1 and its ligand (anti-PD-1/PD-L1) provide significant survival benefits in many cancers, but the efficacy of these treatments varies considerably across different cancer types. Identifying the underlying variables associated with this cancer type-specific response remains an important open research challenge. Objective: To evaluate systematically a multitude of neoantigen-, checkpoint-, and immune response-related variables to determine the key variables that accurately predict the response to anti-PD-1/PD-L1 therapy across different cancer types. Design, Setting, and Participants: This analysis of a broad range of data used whole-exome and RNA sequencing of 7187 patients from the publicly available Cancer Genome Atlas and the objective response rate (ORR) data of 21 cancer types obtained from a collection of clinical trials. Thirty-six variables of 3 distinct classes considered were associated with (1) tumor neoantigens, (2) tumor microenvironment and inflammation, and (3) the checkpoint targets. The performance of each class of variables and their combinations in predicting the ORR to anti-PD-1/PD-L1 therapy was evaluated. Accuracy of predictions was quantified with Spearman correlation measured using a standard leave-one-out cross-validation, a statistical method of evaluating a statistical model by dividing data into 2 segments: one to train the model and the other to validate the model. Data were collected from October 19 through 31, 2018, and were analyzed from November 1 through December 14, 2018. Main Outcomes and Measures: Response to anti-PD-1/PD-1 therapy. Results: Among the 36 variables, estimated CD8+ T-cell abundance was the most predictive of the response to anti-PD-1/PD-L1 therapy across cancer types (Spearman R = 0.72; P < 2.3 × 10-4), followed by the tumor mutational burden (Spearman R = 0.68; P < 6.2 × 10-4), and the fraction of samples with high PD1 gene expression (Spearman R = 0.68; P < 6.9 × 10-4). Notably these top 3 variables cover the 3 classes considered, and their combination is highly correlated with response (Spearman R = 0.90; P < 4.1 × 10-8), explaining more than 80% of the ORR variance observed across different tumor types. Conclusions and Relevance: That we know of, this is the first systematic evaluation of the different variables associated with anti-PD-1/PD-L1 therapy response across different tumor types. The findings suggest that the 3 key variables can explain most of the observed cross-cancer response variability, but their relative explanatory roles may vary in specific cancer types.