In rheumatoid arthritis (RA) benefit from non-steroidal anti-inflammatory drugs (NSAIDs) is mediated through inhibition of the cyclo-oxygenase enzyme, thereby decreasing production of the 2 series prostaglandins (PGs). The lipoxygenase enzyme is intact, however, allowing leucotriene (LT) production, e.g., LTB4 (an inflammatory mediator). Treatment with evening primrose oil (EPO) which contains gamma-linolenic acid (GLA) leads to production of the 1 series PGs, e.g., PGE1, which has less inflammatory effects. Also LT production is inhibited. Eicosapentaenoic acid (EPA, fish oil) treatment provides a substrate for PGs and LTs, which are also less inflammatory. In this study 16 patients with RA were given 540 mg GLA/day (EPO), 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil), and 18 patients an inert oil (placebo). The aim of this study was to determine if EPO or EPO/fish oil could replace NSAID treatment in RA. The initial 12 month treatment period was followed by three months of placebo for all groups. Results at 12 months showed a significant subjective improvement for EPO and EPO/fish oil compared with placebo. In addition, by 12 months the patients receiving EPO and EPO/fish oil had significantly reduced their NSAIDs. After 3 months of placebo those receiving active treatment had relapsed. Despite the decrease in NSAIDs, measures of disease activity did not worsen. It is suggested that EPO and EPO/fish oil produce a subjective improvement and allow some patients to reduce or stop treatment with NSAIDs. There is, however, no evidence that they act as disease modifying agents.