An emerging body of literature indicates that Roux-en-Y gastric bypass (RYGB) patients may be at a heightened risk for substance use disorders (SUDs) after surgery. Little is known about how weight loss and psychosocial outcomes of RYGB patients who develop SUD differ from those who do not. The present study compared weight loss and psychosocial outcomes of 26 post-RYGB patients in inpatient SUD treatment with those of 26 RYGB patients who did not evidence problematic substance use in the post-operative period. SUD and control cases were matched on age, sex and time lapse since surgery. No significant differences in % total weight loss or % excess weight loss (EWL) were found between groups. Those in SUD treatment were significantly less likely to meet the surgical failure criteria of <50% EWL but evidenced greater symptoms of depression, higher rates of probable major depressive disorder and poorer quality of life. Our findings indicate that RYGB patients hospitalized for SUDs achieve successful weight loss despite having poor psychosocial outcomes.