Background: To date, there has been little systematic assessment of the quality of care associated with systemic anti-cancer therapy (SACT) delivery across national healthcare systems. We evaluated hospital-level toxicity rates during SACT treatment as a means of identifying variation in care quality. Methods: All colorectal cancer patients receiving SACT within 106 English National Health Service hospitals between 2016 and 2019 were included. Severe acute toxicity rates were derived from hospital administrative data using a validated coding framework. Variation in hospital-level toxicity rates was assessed separately in the adjuvant and metastatic settings. Toxicity rates were adjusted for age, sex, comorbidity, performance status, tumour site, and TNM staging. Results: Of the 8,173 patients receiving SACT in the adjuvant setting, 2,074 (25%) had a toxicity with adjusted hospital-level rates varying from 11% to 49%. Of the 7,683 patients receiving SACT in the metastatic setting, 3,625 (47%) had a toxicity with adjusted hospital-level rates varying from 25% to 67%. Compared to the national mean toxicity rate in the adjuvant cohort, six hospitals were more than 2 standard deviations (2SD) above, and four hospitals were more than 2SD below. Similarly, in the metastatic cohort, six hospitals were more than 2SD above, and seven hospitals were more than 2SD below the national mean toxicity rate. Conclusions: There is substantial variation in hospital-level severe acute toxicity rates in both the adjuvant and metastatic settings, despite comprehensive risk-adjustment. Ongoing reporting of this performance indicator can be used to focus further investigation of toxicity rates and stimulate quality improvement initiatives to enhance care.