Background: Mechanistic data suggest that n-3 PUFAs and endothelial function may interact and play a role in carcinogenesis, but epidemiologic evidence is lacking. Objective: Our objective was to investigate whether the prospective association between soluble intercellular adhesion molecule-I (sICAM-1) and cancer risk is modulated by n-3 PUFA intake. Design: A nested case-control study was designed to include all first-incident cancer cases diagnosed in the SUpplementation en VItamines et Mineraux AntioXydants cohort between 1994 and 2007, with available dietary data from 24-h records (n = 408). Cases were matched with 1 or 2 randomly selected controls (n = 760). Conditional logistic regression was used to estimate ORs and 95% CIs for the association between prediagnostic plasma concentrations of sICAM-1 and cancer risk, stratified by n-3 PUFA intake. The interactions between sICAM-1 and n-3 PUFA intake were tested. Results: An interaction was observed between sICAM-1 and n-3 PUFA intake, which was consistent across the studied cancer locations (P-interaction = 0.036 for overall, 0.038 for breast, and 0.020 for prostate cancer risk). sICAM-1 concentrations were positively associated with cancer risk among subjects with n-3 PUFA intakes below the median (multivariate ORTertile3vsTertile1: 2.8; 95% CI: 1.5, 5.2; P-trend = 0.001), whereas this association was not observed for subjects with n-3 PUFA intakes above the median (ORTertile3vsTertile1: 1.3; 95% CI: 0.8, 2.3; P-trend = 0.3). Conclusion: These findings suggest that n-3 PUFA intake may counteract the procarcinogenic actions of sICAM-1. This trial was registered at clinicaltrials.gov as NCT00272428. Am J Clin Nutr 2012;95:944-50.