Despite its overall excellent outcomes, weight loss after Roux-en-Y gastric bypass (RYGB) is highly variable. We conducted this study to identify clinical predictors of weight loss after RYGB. We reviewed charts from 300 consecutive patients who underwent RYGB from August 1999 to November 2002. Data collected included patient demographics, medical comorbidities, and diet history. Of the 20 variables selected for univariate analysis, 9 with univariate P values ≤ 0.15 were entered into a multivariable regression analysis. Using backward selection, covariates with P < 0.05 were retained. Potential confounders were added back into the model and assessed for effect on all model variables. Complete records were available for 246 of the 300 patients (82%). The patient characteristics were 75% female, 93% white, mean age of 45 years, and mean initial BMI of 52.3 kg/m2. One year after surgery, patients lost an average of 64.8% of their excess weight (s.d. = 20.5%). The multivariable regression analysis revealed that limited physical activity, higher initial BMI, lower educational level, diabetes, and decreased attendance at postoperative appointments had an adverse effect on weight loss after RYGB. A model including these five factors accounts for 41% of the observed variability in weight loss (adjusted r2 = 0.41). In this cohort, higher initial BMI and limited physical activity were the strongest predictors of decreased excess weight loss following RYGB. Limited physical activity may be particularly important because it represents an opportunity for potentially meaningful pre- and postsurgical intervention to maximize weight loss following RYGB.