The aim of this study was to test the hypothesis of an association between the −30G>A polymorphism of the promoter of the glucokinase gene and the prevalence and incidence of obesity. We studied the −30G>A polymorphism of the glucokinase gene promoter in 981 persons, of whom 866 were seen again 6 years later. All the persons underwent an oral glucose-tolerance test and the BMI (weight/height2) was recorded. The −30G>A polymorphism of the glucokinase gene promoter was studied using RFLP-PCR. At the initial study, the probability of having a BMI ≥25 in carriers of the A allele was significantly lower than expected by chance (odds ratio (OR) = 0.63; 95% confidence interval (CI) = 0.456–0.885). In those persons with a BMI ≥30 at the first study, the probability at 6 years of losing weight (reaching a BMI < 30) was greater in carriers of the A allele (OR = 0.22; 95% CI = 0.087–0.576). The increase in weight over these 6 years, taken as a continuous variable, was significantly less only in those persons who were originally obese (P = 0.018). In conclusion, in a population from southern Spain, carriers of the A allele of the −30G>A polymorphism in the promoter of the glucokinase gene had a lower risk for obesity and the likelihood of losing weight was greater in those obese persons who had the A allele (GA or AA).