PURPOSE: Immediate implant-based breast reconstruction is the leading technique for post-mastectomy reconstruction. Although implants are generally placed beneath the pectoralis major muscle, recent developments have allowed for implant placement above the muscle in a prepectoral plane. In fact, prepectoral breast reconstruction has been shown to mitigate complications associated with subpectoral breast reconstruction, including animation deformity and discomfort. Still, few studies have reported long term outcomes of prepectoral implant placement in the context of direct-to-implant (DTI) breast reconstruction. This study aimed to compare safety outcome endpoints between prepectoral and subpectoral DTI reconstruction. We hypothesized that prepectoral DTI breast reconstruction is a safe alternative to subpectoral DTI breast reconstruction. METHODS: Retrospective chart review at a tertiary academic medical institution identified 115 patients who underwent prepectoral DTI reconstruction and 142 patients who underwent subpectoral DTI reconstruction over a 5-year period. Univariate analysis was performed to compare patient characteristics between both cohorts. A penalized logistic regression identified relationships between postoperative complications and covariate variables in each group. RESULTS: A binomial regression model revealed that prepectoral DTI breast reconstruction is associated with lower risk of surgical site infection (p = 0.04) and lower risk of revision (p = 0.01) when compared to subpectoral DTI breast reconstruction. Rates of capsular contracture, explant, skin necrosis, and hematoma were comparable between groups. CONCLUSION: This study compared the safety outcomes and risk factors in prepectoral and subpectoral DTI reconstruction patient cohorts. These findings support the hypothesis that prepectoral DTI breast reconstruction is a safe alternative to subpectoral DTI breast reconstruction, where the analysis revealed that patients who underwent prepectoral DTI reconstruction experienced lower rates of surgical site infection. It is speculated that the significant difference in surgical site infection may be due to decreased procedure time of the prepectoral procedure, or decreased dissection with preservation of the pectoralis major muscle and vascular network. Prepectoral DTI patients also presented with significantly lower rates of revision when compared to subpectoral DTI patients. Ultimately, this study demonstrated that prepectoral DTI breast reconstruction has a favorable safety profile when compared to supbectoral DTI reconstruction. Prospective study of prepectoral DTI is in progress to collect patient reported outcomes to further delineate safety and efficacy of this breast reconstruction approach.