Objective: The present study was designed to test the hypotheses that response expectancies and emotional distress mediate the effects of an empirically validated presurgical hypnosis intervention on postsurgical side effects (i.e., pain, nausea, and fatigue). Method: Women (n = 200) undergoing breast-conserving surgery (mean age = 48.50 years; 63% White, 15% Hispanic, 13% African American, and 9% other) were randomized to a hypnosis or to an attention control group. Prior to surgery, patients completed assessments of hypothesized mediators (response expectancies and emotional distress), and following surgery, patients completed assessments of outcome variables (pain, nausea, and fatigue). Results: Structural equation modeling revealed the following: (a) Hypnotic effects on postsurgical pain were partially mediated by pain expectancy (p < .0001) but not by distress (p = .12); (b) hypnotic effects on postsurgical nausea were partially mediated by presurgical distress (p = .02) but not by nausea expectancy (p = .10); and (c) hypnotic effects on postsurgical fatigue were partially mediated by both fatigue expectancy (p = .0001) and presurgical distress (p = .02). Conclusions: The results demonstrate the mediational roles of response expectancies and emotional distress in clinical benefits associated with a hypnotic intervention for breast cancer surgical patients. More broadly, the results improve understanding of the underlying mechanisms responsible for hypnotic phenomena and suggest that future hypnotic interventions target patient expectancies and distress to improve postsurgical recovery.