To determine the relationship between family history of diabetes (FHD) and decrease in percent of HOMA beta-cell function (HOMA-beta%) index in healthy betanon-obese Mexican subjects.Forty-eight individuals (30 women and 18 men) with FHD were compared vs 48 control subjects (30 women and 18 men) in a cross-sectional study matched by age, sex, and Waist-to-Hip ratio. Pregnancy, obesity, being overweight, alcohol consumption, high blood pressure, and heavy physical activity were exclusion criteria. All the participants were required to have a Body Mass Index < 25 kg/m2 and serum fasting and 2-hours postload glucose levels lower than 6.1 mmol/l and 7.8 mmol/l, respectively. The reciprocal of serum fasting insulin concentrations (1/Ins0) (microU/ml) and HOMA-B% index were used as indicators of insulin sensitivity and beta-cell function.Average age was of 19.4 +/- 3.6 vs 19.8 +/- 2.6, P = 0.66 for the subjects with and without FHD. HOMA-beta% index was significantly lower in the subjects with FHD (186.1 +/- 74.1 vs 252.7 +/- 149.5, P = 0.01). For similar levels of insulin sensitivity, subjects with FHD showed lower HOMA-beta% index than control subjects (P < 0.001). Multivariate regression analysis showed a strong and independent relationship between FHD and decrease of HOMA-beta% index (OR 2.6, CI95% 1.2-4.3, P = 0.01).This study shows that normal-weight offspring of type 2 diabetes subjects exhibited a significant decrease of HOMA-beta% index suggesting that FHD exerts an independent early negative effect on beta-cell function.