Animal studies have shown that dietary methionine restriction selectively inhibits growth of a variety of human tumor xenografts but has relatively few deleterious effects on normal tissues. The objectives of the present study were to determine whether enteral methionine restriction is safe and tolerable in adults with metastatic cancer and whether it reduces plasma methionine levels. Eight patients with a variety of metastatic solid tumors were enrolled in a phase I clinical trial. A commercially available methionine-free medical food served as the primary dietary protein source for all patients. Patients were prescribed diets containing 0.6-0.8 g of protein, 25-35 kcal, and 2 mg of methionine per kilogram per day. Participants remained on the experimental diet for an average of 17.3 wk (range 8-39 wk). Plasma methionine levels fell from 21.6 +/- 7.3 to 9 +/- 4 microM within 2 wk, representing a 58% decline. Serum albumin and prealbumin levels remained stable or increased. Mean energy intake increased during participation compared with baseline, and protein intake was maintained at target levels. The only side effect was weight loss of approximately 0.5% of body mass index (0.5 kg) per week. We conclude that enteral dietary methionine restriction is safe and tolerable in adults with metastatic solid tumors and results in significant reduction in plasma methionine levels.