The aim of this article is to determine the effectiveness of long-term lifestyle interventions for the prevention of weight gain and morbidity in adults. Prevention of weight gain is important in adults who are of normal weight, overweight and obese. A systematic review of controlled trials of lifestyle interventions in adults with a body mass index of less than 35 kg m−2 with at least 2 years of follow-up was carried out. Eleven of 39 comparisons produced significant improvement in weight between groups at 2 years or longer with mean difference weight change ranging from −0.5 to −11.5 kg. Effective interventions included a 600 kcal/day deficit diet deficit/low-fat diet (with and without meal replacements), low-calorie diet, Weight Watchers diet, low-fat non-reducing diet, diet with behaviour therapy, diet with exercise, diet with exercise and behaviour therapy. Adding meal replacements to a low-fat diet (with and without exercise and behaviour therapy) produced significant improvement in weight. Head-to-head interventions failed to show significant effect on weight with the exception of a Mediterranean diet with behaviour therapy compared with low-fat diet. Diet with exercise and/or behaviour therapy demonstrated significant reduction in hypertension and improvement in risk of metabolic syndrome and diabetes compared with no treatment control. Lifestyle interventions demonstrated significant improvement in weight, reduction in hypertension and reduction in risk of type 2 diabetes and the metabolic syndrome.