Background: Studies evaluating new systemic agents tend to report severe toxicities only, while the cumulative effect of multiple lower grade adverse events (AEs) may have an additional negative impact on patient quality of life (QOL). In the current observational cohort study, we evaluated whether, in patients with metastatic colorectal cancer receiving first-line chemotherapy, cumulative toxicity comprising all grades of AEs is more predictive for QOL than cumulative toxicity due to only high-grade AEs. Methods: One hundred and five patients starting treatment completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) questionnaire at baseline and 10 weeks. AEs, clinical outcomes, and demographics were retrieved from patient records. Cumulative toxicity scores were calculated in three ways: total number of high-grade AEs, total number of all-grade AEs, and total number of AEs multiplied by their grade (the severity score). Relations between cumulative toxicity scores and QOL were studied using multivariable linear regression analyses. Results: The mean age of patients was 65 years, 68% were male, and 84% received oxaliplatin-based chemotherapy. A higher total number of AEs of all grades (B=−2.4, 95% CI=–3.9; –0.9) and the severity score (B=–1.4, 95% CI=–2.3; –0.5) were predictive for clinically relevant changes in physical QOL, whereas the total high-grade AEs was not. None of the cumulative toxicity scores were predictive for global QOL. Conclusion: Cumulative toxicity scores comprising all grades of AEs provide a better measure of treatment burden than a toxicity score comprising high-grade AEs only. Physical QOL seems to be more affected by AEs than global QOL. Our results emphasize that future clinical trials should present cumulative toxicity scores comprising all AE grades as well as physical QOL instead of global QOL.