The purpose of this study was to determine whether gamma-linolenate (GLA) supplementation would suppress weight regain following major weight loss. Fifty formerly obese humans were randomized into a double-blind study and given either 890 mg/d of GLA (5 g/d borage oil) or 5 g/d olive oil (controls) for 1 y. Body weight and composition and adipose fatty acids of fasting subjects were assessed at 0, 3, 12, and 33 mo. After 12 subjects in each group had completed 1 y of supplementation, weight regain differed between the GLA (2.17 +/- 1.78 kg) and control (8.78 +/- 2.78 kg) groups (P < 0.03). The initial study was terminated, and all remaining subjects were assessed over a 6-wk period. Unblinding revealed weight regains of 1.8 +/- 1.6 kg in the GLA group and 7.6 +/- 2.1 kg in controls for the 13 and 17 subjects, respectively, who completed a minimum of 50 wk in the study. Weight regain did not differ in the remaining 10 GLA and 5 control subjects who completed <50 wk in the study. In a follow-up study, a subgroup from both the original GLA (GLA-GLA, n = 9) and the original control (Control-GLA, n = 14) populations either continued or crossed over to GLA supplementation for an additional 21 mo. Interim weight regains between 15 and 33 mo were 6.48 +/- 1.79 kg and 6.04 +/- 2.52 kg for the GLA-GLA and Control-GLA groups, respectively. Adipose triglyceride GLA levels increased 152% (P < 0.0001) in the GLA group at 12 mo, but did not increase further after 33 mo of GLA administration. In conclusion, GLA reduced weight regain in humans following major weight loss, suggesting a role for essential fatty acids in fuel partitioning in humans prone to obesity.