BACKGROUND: High tumor mutational burden (TMB) predicts checkpoint blockade responsiveness, although the association with outcomes may be nuanced in certain tissue contexts. The correlation between TMB and cytotoxic chemotherapy sensitivity is unknown. This study evaluated the relationship between TMB and outcome in patients with solid tumors receiving cytotoxic chemotherapy. METHODS: University of California San Diego patients who received cytotoxic chemotherapy within one year after biopsy for TMB evaluation were included in a retrospective analysis. Physician notes and imaging reports in the electronic medical record were reviewed to determine clinical benefit and progression-free survival (PFS). RESULTS: Among 1526 patients with TMB availability, there were 294 eligible patients who received chemotherapy. There were no significant differences in TMB between those with stable disease ≥6 months/partial response/complete response versus others (t-test, = .22). There were no significant differences in PFS for patients with TMB <10 vs. TMB ≥10 mutations/Mb (log-rank test, median and 95% CI: 6.0 (4.8-7.4) vs. 5.4 (4.3-6.6) months; = .21). Nor were there significant differences in PFS for patients with a TMB <10 vs. TMB ≥10 mutations/mb for breast ( = .07), lung ( = .47), or gastrointestinal cancer ( = .53). CONCLUSIONS: In summary, TMB was not predictive of stable disease ≥6 months/partial response/complete response or PFS in patients receiving cytotoxic chemotherapy. TRIALS REGISTRATION: NCT02478931.