We retrospectively investigated the pharmacokinetics and exposure‐efficacy/safety relationships of single‐agent atezolizumab based on tissue tumor mutational burden (tTMB) status (high vs low [≥16 vs <16 mutations/megabase]) in a pan‐tumor population from seven clinical trials. Data sources included the OAK, POPLAR, BIRCH, FIR, IMvigor210, IMvigor211, and PCD4989g studies; 986 of 2894 treated patients (34%) had TMB data. Exposure metrics were obtained using a prior two‐compartment intravenous‐infusion population‐pharmacokinetics model, merged with prognostic, biomarker, efficacy, and safety variables. Baseline demographic/clinical characteristics and prognostic factors were well balanced between patients with high (n = 175) and low (n = 811) tTMB. Exposure was similar in the high‐ and low‐tTMB subgroups, with no difference seen in the evaluable vs total treated populations. The objective response rate (ORR) was 29.7% vs 13.4%, complete response rate was 6.9% vs 3.2%, and median duration of response (95% CI) was 29.0 (18.6‐NE) months vs 15.9 (12.5‐20.5) months for patients with high‐tTMB vs low‐tTMB tumors, respectively. A flat exposure‐efficacy relationship was seen for ORR in patients with high‐tTMB based on the cycle 1 minimum atezolizumab concentration and area under the serum concentration time curve (AUC). A nonsignificant exposure‐safety profile was seen for grade 3/4 adverse events and adverse events of special interest based on the AUC of atezolizumab in the high‐tTMB population. tTMB is an additional predictive biological factor affecting response to atezolizumab, and quantitative investigations of atezolizumab exposure and relationships of exposure with safety and efficacy support the use of a 1200‐mg, every 3‐week regimen in a tumor‐agnostic high‐tTMB population.