BACKGROUND: A seroma following prepectoral tissue expander (TE) reconstruction often begets other complications, which may compromise the reconstruction. This study investigated the association between seroma and subsequent complications. METHODS: All consecutive prepectoral TE reconstructions performed between March 2017 and December 2022 at a single center were reviewed. Demographics, operative characteristics, and complications data were extracted for all patients and analyzed. RESULTS: Two hundred patients (318 breasts) underwent reconstruction and were, on average, 53 years of age, nonsmokers (98%), and nondiabetic (91%), with a body mass index of 26 kg/m. Seventy-six (24%) breasts were radiated, and 93 (47%) patients received chemotherapy. All 318 breasts underwent immediate reconstruction following prophylactic (34%) or therapeutic (66%) mastectomies. Seroma occurred in 50 (16%) breasts and was associated with higher body mass index (30 versus 27 kg/m, < 0.05) and higher mastectomy weight (662 versus 515 g, < 0.05). Half of all breasts with a seroma (24 of 50, 49%) went on to develop other complications. Infection and explantation commonly followed, occurring in 18 (36%) and 21 (42%) breasts with a prior seroma, respectively. In adjusted multivariable models, prior seroma was associated with 9 times higher odds of infection (odds ratio 9.2; 95% confidence interval, 4-21, < 0.01) and 7 times higher odds of explantation (odds ratio 6.8, 95% confidence interval, 3-17, < 0.01). CONCLUSIONS: Although causality cannot be determined, our data suggests that seroma may be the "kiss of death" in prepectoral TE reconstruction because half of all breasts with a seroma went on to develop other complications.