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The aim of this study was to determine a potential benefit of the specific psychoeducational intervention “Learning to Live with Cancer” (LTLWC) for patients with operated nonmetastatic breast cancer, with respect to psychological variables and endocrine and immune parameters.Fifty-two postmenopausal women with operated stage I to III breast cancer were randomized to either a breast cancer intervention group (BCIG, n = 30) who immediately began participating in the LTLWC intervention program or to a breast cancer control group (BCCG, n = 22). Matched healthy women were asked to participate as a noncancer comparison group (n = 26). All participants were evaluated at three different time points (t1–t3) using a set of standardized questionnaires and blood samples were taken to analyze immune cell subsets and stress hormone levels.A significant reduction in trait anxiety/State Trait Anxiety Inventory score was observed in the BCIG (t1: median = 35.0 [interquartile range = 28.0–38.0] versus t3: median = 26.0 [interquartile range = 18.5–37.0], p = .0001) compared with the BCCG (t1: median = 41.0 [interquartile range =32.75–49.0]; t3: median = 38.5 [interquartile range = 30.75–46.5], p = .01524; p interaction = .001). In parallel, a significant rise of serotonin levels (t1: median = 66.5 ng/ml [interquartile range = 11.50–106.00] versus t3: median = 80.5 ng/ml [interquartile range =59.00–118.00], p = .00008) as well as a significant reduction of the elevated number of Treg cells at baseline (t1: median = 4.45% [interquartile range = 4.00–5.33] versus t3: median = 2.80% [interquartile range = 2.68–3.13], p < .00001) were observed in the BCIG versus no change in the BCCG. A significant statistical association between reduced trait anxiety and decreased Treg cell number could be demonstrated in the BCIG (r = .62, p < .01).The observed results of this study provide preliminary support for the efficacy of the LTLWC program in significantly improving psychoneuroimmunological parameters in patients with nonmetastatic breast cancer.