Having shown in a 20-week placebo-controlled double-blind crossover trial that ‘global’ antioxidant supplementation - including selenium, &bgr;-carotene, vitamin C (ascorbic acid), vitamin E (tocopherol) and methionine - curbs symptoms while correcting oxidative stress in patients with recurrent nongallstone pancreatitis, we have investigated through two further trials the relative importance of methionine versus that of the other antioxidants in effecting this good outcome. 30 consecutive patients were entered into the second study in which therapeutic intervention involved only the active metabolite of methionine,S-adenosylmethionine (SAMe), 2.4g per day in divided doses. Blood analysis showed that subnormal baseline levels of selenium, &bgr;-carotene and vitamins E and C were unchanged throughout and that drug treatment resulted in supranormal levels of SAMe in plasma. SAMe proved to be ineffective clinically as judged by attack rate and background pain, as well as biochemically as gauged by the percentages of oxidatively altered vitamin C and linoleic acid. The coadministration of selenium and &bgr;-carotene with SAMe was tested in the third study. This was abandoned when 3 patients had a clearcut attack of pancreatitis while on subsequent ‘open’ treatment. Analysis of clinical and biochemical information from 14 patients who had completed the 20-week trial confirmed the inefficacy of the combination, although active treatment normalised serum selenium and &bgr;-carotene concentrations while SAMe levels were again pushed into the supranormal range. The results show that SAMe on its own, or with additional selenium and &bgr;-carotene, is ineffective in patients with recurrent nongallstone pancreatitis. By a process of elimination with reference to biochemical measurements during the 3 trials, and considering experimental evidence of the importance of methionine for pancreatic integrity, we cautiously suggest that an effective antioxidant prescription should include SAMe (or methionine) as well as vitamin C, with additional compounds as indicated by blood measurements.