The risk of coronary heart disease (CHD) is influenced by family history, insulin sensitivity (IS), and diet. Adiposity affects CHD and IS. The cellular mechanism of IS is thought to involve the adipocyte cytokine tumor necrosis factor-alpha (TNF-alpha). Insulin-stimulated glucose uptake in isolated subcutaneous and omental adipocytes obtained during elective surgery was measured in 61 premenopausal women, 24 with a parental history (PH) of CHD. In vivo IS was measured using the short insulin tolerance test (SITT) in 28 women, 16 with PH-CHD, before and 3 weeks after randomization to a low glycemic index (LGI) or high glycemic index (HGI) diet. In vitro adipocyte IS and TNF-alpha production was measured following dietary modification. On the habitual diet, in vitro insulin-stimulated glucose uptake in adipocytes as a percentage increase over basal was less in women with PH-CHD than in those without it (presented as the median with 95% confidence limits: subcutaneous, 28% (17% to 39%) v 96% (70% to 120%), P < .01); omental, 40% (28% to 52%) v 113% (83% to 143%), P < .01). In vivo IS in 16 PH-CHD subjects and 12 controls before dietary randomization was similar, and increased in both groups consuming a LGI versus HGI diet (PH-CHD, 0.31 (0.26 to 0.37) v 0.14 (0.10 to 0.24) mmol/L/min, P < .01; controls, 0.31 (0.1 to 0.53) v 0.15 (0.06 to 0.23) mmol/L/min, P < .05). Adipocyte IS was greater in PH-CHD women on a LGI versus HGI diet (subcutaneous, 50% (20% to 98%) v 13% (1% to 29%); omental, 97% (47% to 184%) v 29% (4% to 84%), P < .05). Adipocyte TNF-alpha production was higher in women with versus without PH-CHD (subcutaneous, 0.3 (0.18 to 0.42) v 0.93 (0.39 to 1.30) ng/mL/min; visceral, 0.22 (0.15 to 1.30) v 0.64 (0.24 to 1.1) ng/mL/min, P < .04, respectively), but was uninfluenced by the dietary glycemic index. We conclude that in vitro adipocyte IS is reduced and adipocyte TNF-alpha production is increased in premenopausal women with PH-CHD. A LGI diet improves both adipocyte IS in women with PH-CHD and in vivo IS in women with and without PH-CHD.