We have examined the relationship between artificially sweetened beverage (ASB) consumption and long-term weight gain in the San Antonio Heart Study. From 1979 to 1988, height, weight, and ASB consumption were measured among 5,158 adult residents of San Antonio, Texas. Seven to eight years later, 3,682 participants (74% of survivors) were re-examined. Outcome measures were incidence of overweight/obesity (OW/OBinc) and obesity (OBinc) (BMI ≥ 25 and ≥ 30 kg/m2, respectively), and BMI change by follow-up (ΔBMI, kg/m2). A significant positive dose-response relationship emerged between baseline ASB consumption and all outcome measures, adjusted for baseline BMI and demographic/behavioral characteristics. Consuming >21 ASBs/week (vs. none) was associated with almost-doubled risk of OW/OB (odds ratio (OR) = 1.93, P = 0.007) among 1,250 baseline normal-weight (NW) individuals, and doubled risk of obesity (OR = 2.03, P = 0.0005) among 2,571 individuals with baseline BMIs <30 kg/m2. Compared with nonusers (+1.01 kg/m2), ΔBMIs were significantly higher for ASB quartiles 2–4: +1.46 (P = 0.003), +1.50 (P = 0.002), and +1.78 kg/m2 (P < 0.0001), respectively. Overall, adjusted ΔBMIs were 47% greater among artificial sweetner (AS) users than nonusers (+1.48 kg/m2 vs. +1.01 kg/m2, respectively, P < 0.0001). In separate analyses—stratified by gender; ethnicity; baseline weight category, dieting, or diabetes status; or exercise-change category—ΔBMIs were consistently greater among AS users. These differences, though not significant among exercise increasers, or those with baseline diabetes or BMI >30 kg/m2 (P = 0.069), were significant in all 13 remaining strata. These findings raise the question whether AS use might be fueling—rather than fighting—our escalating obesity epidemic.