The importance of the relative dietary content of protein, carbohydrate and the type of carbohydrate (that is, glycemic index (GI)) for weight control under ad libitum conditions has been controversial owing to the lack of large scale studies with high diet adherence. The Diet, Obesity and Genes (DioGenes) European multicentre trial examined the importance of a slight increase in dietary protein content, reduction in carbohydrate and the importance of choosing low (LGI) vs high GI (HGI) carbohydrates for weight control in 932 obese families. Only the adults underwent a diet of 800 kcal per day for 8 weeks, and after losing ~11kg they were randomized to one of five energy ad libitum diets for 6 months. The diets differed in protein content and GI. The high-protein (HP) diet groups consumed 5.4% points more energy from protein than the normal protein (NP) groups, and the LGI diet groups achieved 5.1% lower GI than the HGI groups. The effect of HP and LGI was additive on weight loss and maintenance, and the combination was successful in preventing weight regain and reducing drop-out rate among the adults after the 11kg weight loss. This diet also reduced body fatness and prevalence of overweight and obesity among their children and had consistent beneficial effects on blood pressure, blood lipids and inflammation in both parents and children. After 1 year, mainly the HP effects were maintained. Putative genes have been identified that suggest this diet to be particularly effective in 67% of the population. In conclusion, the DioGenes diet has shown to be effective for prevention of weight regain and for weight reduction in overweight children under ad libitum conditions. The less-restrictive dietary approach fits into a normal food culture, and has been translated into popular diet and cook books in several languages.