BACKGROUND: Family history of colon cancer often portends increased risk of disease development; however, the prognostic significance of family history related to disease and survival outcomes is unclear. METHODS: To investigate the relationship between family history of colorectal cancer and survival outcomes in stage III colon cancer patients, a prospective cohort of 1,935 patients with resected stage III colon cancer enrolled in a randomized controlled trial (N0147), comparing the standard of care FOLFOX to FOLFOX with cetuximab, was studied. Patients completed a baseline questionnaire on family history and were followed every 6 months until death or 5 years after randomization. RESULTS: We examined the endpoints of disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS), comparing patients with a positive versus negative family history of colorectal cancer. The adjusted hazard ratios (HRs) for patients with a positive family history were 0.95 [95% confidence interval (CI), 0.78-1.16] for DFS, 0.94 (95% CI, 0.76-1.16) for TTR, and 0.92 (95% CI, 0.74-1.15) for OS (all adjusted P>0.47). A non-significant trend toward improved DFS (P=0.17; adjusted P=0.34) was observed when 2 or more relatives were affected as compared to 0 relatives (multivariate HR: 0.72; 95% CI, 0.45-1.15), whereas subjects with histories of 0 or 1 affected relatives had similar DFS (multivariate HR for 1 vs. 0: 1.00; 95% CI, 0.81-1.24). Interactions of the molecular factors KRAS, BRAF, and MMR with family history were also explored. The only significant interaction was for deficient MMR (dMMR) and first-degree relatives with a family history of colorectal cancer (0 vs. 1 vs. 2+ relatives) for a benefit on OS (univariate P=0.001), which remained significant after adjusting for other factors (P=0.029). CONCLUSIONS: Among patients with stage III resected colon cancer treated with adjuvant FOLFOX, a family history of colorectal cancer did not significantly impact DFS, TTR, or OS outcomes, with the exception of patients with dMMR-expressing tumors.