The relationships of rate of weight gain and weight fluctuation to incidence of non-insulin-dependent diabetes mellitus (NIDDM) were examined in Pima Indians. The 1,458 subjects were participants in a prospective study with examinations approximately every 2 years. Rate of weight gain was defined as the slope of the regression line of weight with time for two or more consecutive examinations > or = 2 years apart and weight fluctuation as the root-mean-square departure from this line for four examinations. Among men, incidence of NIDDM was strongly and significantly related to rate of weight gain (e.g., age-adjusted incidence = 56.7/1,000 person-years in those with weight gain > or = 3 kg/year and 16.9/1,000 person-years for those losing weight [Ptrend < 0.01]). In women, weight gain was significantly related to diabetes incidence only in those who were not initially overweight (body mass index < 27.3 kg/m2). In contrast to the relationship with weight gain, weight fluctuation was not associated with incidence of diabetes in either sex. These findings suggest that weight control in overweight individuals may be a more effective strategy for prevention of NIDDM in men than in women, whereas prevention of obesity may prevent diabetes in both sexes. Concern about a diabetogenic effect of weight fluctuation should not deter weight-control efforts.