BackgroundColorectal cancer remains the third leading cause of cancer-related mortality in the United States. This study evaluates the causes of death in patients operated on for colorectal cancer and their determinants. MethodsAn Instructional Review Board-approved database containing patients who underwent surgical resection for colorectal cancer from 2004 to 2018 (last followed up in December 2020) in a tertiary care institution. Data on the underlying cause of death was extracted from the Registry of Vital Records and Statistics in Massachusetts. ResultsA total of 576 deaths were recorded in the database, of which 290 (50.35%) patients died of colorectal cancer. Deaths from colorectal cancer gradually decreased over time, whereas deaths from other cancers increased, and deaths from cardiovascular diseases remained stable. Patients who died from colorectal cancer were younger, died earlier in the disease course, had fewer comorbidities, higher rates of stage IV disease, rectal cancer, neoadjuvant therapy, extramural vascular invasion, perineural invasion, R0 resection, and preserved mismatch repair protein status. On multivariate analysis, age (adjusted odds ratio for 10-year increase = 0.79, 95% confidence interval 0.65–0.95), American Society of Anesthesiologists score (adjusted odds ratio = 0.64, confidence interval 0.42–0.98), stage IV disease (adjusted odds ratio = 3.02, confidence interval 1.59–5.9), neoadjuvant therapy (adjusted odds ratio = 7.91, confidence interval 2.64–28.13), extramural vascular invasion (adjusted odds ratio = 2.3, confidence interval 1.36–3.91) & time from diagnosis to death (adjusted odds ratio = 0.76, confidence interval 0.68–0.83) predicted death due to colorectal cancer versus other causes, whereas tumor location, perineural invasion, R0 resection, and mismatch repair protein status did not. ConclusionThere is a declining trend of deaths from colorectal cancer, presumably reflecting advances in colorectal cancer management strategies and better screening over time. However, younger patients disproportionately contribute to death due to colorectal cancer and need aggressive screening and management strategies.