Background: Replacement of caloric beverages with noncaloric beverages may be a simple strategy for promoting modest weight reduction; however, the effectiveness of this strategy is not known. Objective: We compared the replacement of caloric beverages with water or diet beverages (DBs) as a method of weight loss over 6 mo in adults and attention controls (ACs). Design: Overweight and obese adults [n = 318; BMI (in kg/m2): 36.3 ± 5.9; 84% female; age (mean ± SD): 42 ± 10.7 y; 54% black] substituted noncaloric beverages (water or DBs) for caloric beverages (≥200 kcal/d) or made dietary changes of their choosing (AC) for 6 mo. Results: In an intent-to-treat analysis, a significant reduction in weight and waist circumference and an improvement in systolic blood pressure were observed from 0 to 6 mo. Mean (±SEM) weight losses at 6 mo were −2.5 ± 0.45% in the DB group, −2.03 ± 0.40% in the Water group, and −1.76 ± 0.35% in the AC group; there were no significant differences between groups. The chance of achieving a 5% weight loss at 6 mo was greater in the DB group than in the AC group (OR: 2.29; 95% CI: 1.05, 5.01; P = 0.04). A significant reduction in fasting glucose at 6 mo (P = 0.019) and improved hydration at 3 (P = 0.0017) and 6 (P = 0.049) mo was observed in the Water group relative to the AC group. In a combined analysis, participants assigned to beverage replacement were 2 times as likely to have achieved a 5% weight loss (OR: 2.07; 95% CI: 1.02, 4.22; P = 0.04) than were the AC participants. Conclusions: Replacement of caloric beverages with noncaloric beverages as a weight-loss strategy resulted in average weight losses of 2% to 2.5%. This strategy could have public health significance and is a simple, straightforward message. This trial was registered at clinicaltrials.gov as NCT01017783.