We showed previously that 64% of the total dietary sulfur amino acid (SAA) requirement could be supported by dietary cysteine (Cys). However, the observation of such a sparing effect may be affected by the dietary intakes of SAA provided. The aim of this study was to compare methionine (Met) metabolism and transsulfuration (TS) in five healthy men fed three different diets (in random order) for 3 d each, with varying combinations of Met and Cys: 24 mg Met/(kg. d) and no Cys (diet A); 13 mg Met/(kg. d) and 11 mg Cys/(kg. d) (diet B); and 5 mg Met/(kg. d) and 19 mg Cys/(kg. d) (diet C). On d 3, Met kinetics and TS were assessed using orally administered L-[1-(13)C, methyl-(2)H(3)]methionine. Met demethylation (transmethylation, TM) significantly decreased as the dietary Met to Cys ratio decreased. Met TS was significantly lower during diets B [2.8 +/- 0.4 micro mol/(kg. h)] and C [1.5 +/- 0.5 micro mol/(kg. h)] than during diet A [7.8 +/- 2.9 micro mol/(kg. h)] (P < 0.05). The results of the present study indicate that when the ratio of Met to Cys fed is typical of that found in major food proteins and total SAA are sufficient to meet requirements, TS is significantly reduced compared with the case in which SAA needs are supplied by Met alone. We conclude that Cys sparing occurs through an increase in the fraction of the homocysteine pool destined for RM relative to TS (RM:TS).