RGS2 is a negative regulator of Galpha protein signaling and promotes adipocyte differentiation. Recently, we described a polymorphism at the C1114G locus with the G allele associated with hypertension in a cross-sectional study. The aim of the present study was to assess whether the RGS2 C1114G is predictive of overweight in young subjects with grade I hypertension. We genotyped at the RGS2 C1114G locus 406 (male, n = 294; female, n = 112) white hypertensive subjects (age, 33 +/- 9 years) never treated for hypertension and at low cardiovascular risk. Median follow-up was 7.85 years. At baseline, male patients carrying the RGS2 1114G allele had higher body mass index (BMI) than patients with CC genotype (26.1 +/- 0.3 vs 25.3 +/- 0.3 kg/m2, P < .05). The frequency of male patients with BMI > or = 25 was similar between the patients with G allele and those with CC genotype (55.1% vs 47.8%, P = not significant). No significant difference between the 2 groups was observed with regard to physical activity, blood pressure, and heart rate. At the end of follow-up, BMI was higher in male patients with G allele compared with patients with CC genotype (26.8 +/- 0.3 vs 25.8 +/- 0.2 kg/m2, P < .01); and the frequency of male patients with BMI >25 kg/m2 was greater in the former (69.0% vs 52.2%, P < .01). According to Cox regression, allele G was a significant predictor of developing overweight or obesity during follow-up. These epidemiologic relations were not significant in female patients. In young male patients with grade I hypertension, RGS2 1114G allele is associated with increased BMI and with greater risk of developing overweight or obesity. The RGS2 1114G allele may be considered a genetic marker that predicts an individual's predisposition to gaining weight.