In this study, we examined the association between sugar-sweetened drink, diet soda, and fruit juice consumption and surrogate measures of insulin resistance. Sugar-sweetened drink, diet soda, and fruit juice consumption was estimated using a semiquantitative FFQ in 2500 subjects at the fifth examination (1991-1995) of the Framingham Offspring Study. Surrogate markers of insulin resistance measured in this study included fasting insulin, fasting glucose, homeostatic model assessment of insulin resistance, and the insulin sensitivity index (ISI(0,120)). Sugar-sweetened drink consumption was positively associated with fasting insulin (none vs. > or = 2 servings/d, 188 vs. 206 pmol/L, P-trend <0.001) after adjusting for potential confounders. Sugar-sweetened drink consumption was not associated with fasting glucose or ISI(0,120). Fruit juice consumption was inversely associated with fasting glucose (none vs. > or = 2 servings/d, 5.28 vs. 5.18 mmol/L, P-trend = 0.006), but not with fasting insulin (none vs. > or = 2 servings/d, 200 vs. 188 pmol/L, P-trend = 0.37) or ISI(0,120) (none vs. > or = 2 servings/d, 26.0 vs. 27.0, P-trend = 0.19) in multivariate models. Diet soda consumption was not associated with any surrogate measures of insulin resistance after adjustment for potential confounders (insulin: none vs. > or = 2 servings/d, 195 vs. 193 pmol/L, P-trend = 0.59; glucose: 5.26 vs. 5.24 mmol/L, P-trend = 0.84; and ISI(0,120): 26.2 vs. 26.7, P-trend = 0.37). In these healthy adults, sugar-sweetened drink consumption appears to be unfavorably associated with surrogate measures reflecting hepatic more than peripheral insulin sensitivity. Studies of long-term beverage consumption using more direct measures of insulin sensitivity are clearly warranted.