Abstract Background Long-chain omega-3 polyunsaturated fatty acids (PUFA) supplementation is used as a therapeutic secondary prevention strategy among post-myocardial infarction (MI) patients. The effects of omega-3 PUFA on markers of energy homeostasis among post-MI patients are unclear. Methods We investigated the effects of Omacor (a pharmaceutical capsule formulation of highly refined, concentrated omega-3 PUFA; Solvay Healthcare, Southampton, UK; 1 g/day) in addition to usual care (cardiovascular therapy) in a pilot randomised study of 35 post-MI men. Following randomisation to Omacor ( n = 16), or ‘usual care’ controls ( n = 19), fasting levels of insulin, non-esterified fatty acids (NEFA), triglycerides, glucose and adipocytokines (adiponectin, leptin and tumour necrosis factor (TNF)-α), as indices of markers of energy homeostasis, were measured at baseline and after 3-month treatment. Results There were no baseline differences in age, body mass index, blood pressure, fasting triglycerides, plasma glucose, NEFA and adipocytokines between the two treatment arms ( P = 0.07). There were no significant changes in metabolically active hormones within groups after 3-month treatment. Across arms, the direction of baseline to follow-up changes in insulin levels were significantly different ( P = 0.03), with a mean increase with Omacor (+ 3.39 mU/ml) and a decrease among controls (− 17.6 mU/ml), without associated deteriorating changes in triglycerides, NEFA or plasma glucose. Conclusion This pilot study suggests that Omacor had little effect on glycaemic control among male post-MI patients. However, Omacor was associated with raised insulin levels, compared to usual care; thus, a metabolic basis for the cardioprotective action of Omacor, outside of its lipid lowering effects, merits further investigation.