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Background: Overweight and obese (OW/OB) body mass index (BMI) is associated with greater inflammation and poorer outcomes in breast cancer (BC). Stress management interventions using cognitive behavioral therapy (CBT) and relaxation training (RT) have reduced inflammation in BC patients but have not been tested specifically in OW/OB patients undergoing primary treatment. We developed brief CBT and RT-based group interventions and tested their effects (vs time-matched Health Education [HE] control) on serum inflammatory cytokines (IL-6, IL-1β and TNF-α) in OW/OB vs normal weight (NW) BC patients during primary treatment. We hypothesized OW/OB women would show higher levels of inflammatory cytokines, and that stress management would decrease these cytokines more in OW/OB women than in NW women. Methods: Stage 0 -III BC patients were enrolled post-surgery and before initiating adjuvant therapy, were randomized to either 5 weeks of CBT, RT, or HE, and provided questionnaires and blood samples at baseline and 6-months. Serum cytokine levels were measured by ELISA. Repeated measures analysis of variance tested the interaction of condition by BMI by time in predicting cytokine levels over 6 months, controlling for age, stage, ethnicity, and income. Results: The sample (N = 153) majority was OW/OB (55.6%). We found differences in baseline IL-6 and IL-1β across BMI categories, with greater IL-6 (p < 0.005) and IL-1β (p < 0.04) in OW and OB vs NW women, but no difference between OW and OB women. There were no differences in baseline TNF-α among BMI groups. BMI category moderated the effect of brief stress management interventions on IL-6 changes over 6-months (p = 0.028): CBT/RT vs HE decreased IL-6 in OW/OB (p = 0.045) but not in NW patients (p = 0.664). There were no effects on IL-1β or TNF-α. Results could not be explained by differences in receipt of adjuvant therapy, prescription medications, or changes in physical activity. Conclusions: OW/OB women with newly diagnosed BC had significantly greater serum IL-6 and IL-1β than NW women post-surgery. Brief stress management delivered with primary treatment among OW/OB patients may reduce the increases in inflammatory markers known to accompany adjuvant treatments and could thus promote better outcomes. Clinical Trial Registration: NCT02103387.