Abstract Background Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods Baseline plasma insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall (OS) and progression-free survival (PFS). P values are two-sided. Results Median follow-up for 1,086 patients was 6.2 years. Compared to patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78, Pnon-linearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82, Ptrend = .003). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted HR for OS of 1.60 (95% CI = 1.30 to 1.97, Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69, Ptrend = < .001). Plasma C-peptide and IGF-I were not associated with patient outcomes. Adiponectin was not associated with OS; there was a non-linear U-shaped association between adiponectin and PFS (Pnon-linearity = .03). Conclusions Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.