The efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in preventing recurrence of atrial fibrillation (AF) is controversial and their effects on inflammation and oxidative stress in this population are not known. This study examined the effects of high-dose marine n-3 PUFAs added to conventional therapy on the recurrence of AF and on markers of inflammation and oxidative stress. Patients with paroxysmal or persistent AF were randomized to n-3 PUFAs (4 g/day; n = 126) or placebo (n = 64) in a 2:1 ratio in a prospective, double-blind, placebo-controlled, parallel group study. The primary outcome was time to recurrence of AF. Secondary outcomes were changes in biomarkers of inflammation (serum interleukin [IL]-6, IL-8, IL-10, tissue necrosis factor alpha, monocyte chemoattractant protein-1, and vascular endothelial growth factor), N-terminal-pro-brain-type natriuretic peptide, and oxidative stress (urinary F₂-isoprostanes). AF recurred in 74 patients (58.7%) randomized to n-3 PUFAs and in 30 patients (46.9%) who received placebo; time to recurrence of AF did not differ significantly in the 2 groups (hazard ratio 1.20; 95% confidence interval 0.76 to 1.90, adjusted p = 0.438). Compared with placebo, n-3 PUFAs did not result in clinically meaningful changes in concentrations of inflammatory markers, N-terminal-pro-brain-type natriuretic peptide or F₂-isoprostanes. In conclusion, in patients with paroxysmal or persistent AF, treatment with n-3 PUFAs 4 g/day did not reduce the recurrence of AF, nor was it associated with clinically important effects on concentrations of markers of inflammation and oxidative stress. (Clinical trial registration number, NCT 00552084.)