The consumption of sucrose-sweetened soft drinks (SSSDs) has been associated with obesity, the metabolic syndrome, and cardiovascular disorders in observational and short-term intervention studies. Too few long-term intervention studies in humans have examined the effects of soft drinks.We compared the effects of SSSDs with those of isocaloric milk and a noncaloric soft drink on changes in total fat mass and ectopic fat deposition (in liver and muscle tissue).Overweight subjects (n = 47) were randomly assigned to 4 different test drinks (1 L/d for 6 mo): SSSD (regular cola), isocaloric semiskim milk, aspartame-sweetened diet cola, and water. The amount of intrahepatic fat and intramyocellular fat was measured with (1)H-magnetic resonance spectroscopy. Other endpoints were fat mass, fat distribution (dual-energy X-ray absorptiometry and magnetic resonance imaging), and metabolic risk factors.The relative changes between baseline and the end of 6-mo intervention were significantly higher in the regular cola group than in the 3 other groups for liver fat (132-143%, sex-adjusted mean; P < 0.01), skeletal muscle fat (117-221%; P < 0.05), visceral fat (24-31%; P < 0.05), blood triglycerides (32%; P < 0.01), and total cholesterol (11%; P < 0.01). Total fat mass was not significantly different between the 4 beverage groups. Milk and diet cola reduced systolic blood pressure by 10-15% compared with regular cola (P < 0.05). Otherwise, diet cola had effects similar to those of water.Daily intake of SSSDs for 6 mo increases ectopic fat accumulation and lipids compared with milk, diet cola, and water. Thus, daily intake of SSSDs is likely to enhance the risk of cardiovascular and metabolic diseases. This trial is registered at clinicaltrials.gov as NCT00777647.