BACKGROUND: Benefits of omega-3 fatty acids in perinatal women are well documented, although fish intake has declined among perinatal women. OBJECTIVE: To determine the tolerability of omega-3 fatty acid supplementation in perinatal women. DESIGN: Pregnant and postpartum women with major depressive disorder (MDD) entered an 8-week double-blind, placebo-controlled trial of omega-3 fatty acids. Four capsules provided 1.84g/day of eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA), or matching placebo (corn oil with 1% fish oil to maintain blind). Tolerability was assessed by clinician interview biweekly. RESULTS: Fifty-nine women enrolled. Thirteen (22%) reported mainly transient side effects including dizziness, diarrhea, nausea, burping, heartburn/reflux, difficulty swallowing capsules, unpleasant breath/bad taste or feeling tired. The most common were unpleasant breath/bad taste and heartburn/reflux. Six reporting side effects received omega-3 fatty acids; seven received placebo. Neither pregnant nor postpartum women discontinued due to intolerability. CONCLUSIONS: Omega-3 fatty acid supplements were well tolerated by perinatal women.