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Introduction: Implant-based immediate breast reconstruction (IBR) is a common surgical procedure in breast cancer patients. Comparative analysis concerning the placement of implants is still lacking. Hence, we aimed to analyze pre- versus subpectoral IBR in breast cancer patients. Patients: A single-center experience with implant-based IBR following skin/nipple-sparing mastectomy was evaluated. Patient demographics, incidence of major complications, and quality of life assessed with BREAST-Q were compared between the pre- and subpectoral cohort. Results: A total of 63 patients were included in this analysis of whom 29 underwent subpectoral and 34 underwent prepectoral IBR. Median duration of surgery was prolonged in the subpectoral versus the prepectoral group (104 +/- 28 vs. 80 +/- 91 min; p < 0.05). The mean number of major complications was significantly increased in the subpectoral group (1.41 +/- 1.76 vs. 0.47 +/- 0.75 per patient; p < 0.05). Detailed analysis showed a significantly increased incidence of implant dislocation (p < 0.05) and a trend concerning capsular contracture (p = 0.086, not significant) and necrosis (p = 0.092, not significant) in the subpectoral group. Quality of life was equal in both groups. Conclusion: The mean number of major complications in the subpectoral group should be considered when IBR is indicated. Prepectoral IBR seems to be a feasible alternative surgical treatment option with less major complications in selected patients.