Background: Nipple-sparing mastectomy offers several advantages for women seeking postmastectomy breast reconstruction, but compromised skin and nipple perfusion may lead to skin and nipple necrosis. It is unclear whether the incisional approach contributes to these complications; therefore, the purpose of this study was to compare the impact of incision type on outcomes in patients undergoing nipple-sparing mastectomy. Methods: This is a prospective cohort study of patients undergoing nipple-sparing mastectomy with prosthetic breast reconstruction through an infra-mammary fold versus a lateral radial incision. Skin and nipple perfusion as represented by fluorescence intensity, mammometric parameters, patient-reported outcomes, and clinical outcomes were analyzed and compared for the two cohorts, and multivariable logistic regression models were performed to evaluate the effects of covariates on outcomes. Results: Seventy-nine patients were studied: 55 in the inframammary fold cohort and 24 in the lateral radial cohort. The inframammary fold group had significantly less fluorescence intensity to the inferior (21.9 percent versus 36.9 percent; p = 0.001) and lateral portions of breast skin (23.1 percent versus 40.7 percent; p = 0.003) after reconstruction. Decreased fluorescence intensity was associated with smoking, decreased mean arterial pressure, and greater specimen weight. Postreconstruction breast volumes were increased over preoperative volumes in the inframammary fold group (38.3 percent) versus the lateral radial (31.2 percent) group; however, patients with a lateral radial incision had a greater increase in satisfaction with their breasts and psychosocial well-being. Conclusions: There are significant differences in patient-reported outcomes and final breast volumes based on the incisional approach to nipple-sparing mastectomy. These data can be used to guide providers and counsel patients considering nipple-sparing mastectomy with prosthetic reconstruction.