Background Post-mastectomy pocket irrigation solution choice is debated and primarily surgeon dependent. We compare triple antibiotic solution (TAS) to 0.05% chlorhexidine gluconate (CHG). Objectives The purpose of this study was to determine surgical site infection (SSI) rates after using TAS vs CHG for breast pocket irrigation in immediate tissue expander breast reconstruction. Methods A prospective, blinded, randomized controlled trial was performed in patients (18-81 years old) undergoing bilateral mastectomy with tissue expander (TE) reconstruction. In each patient, one mastectomy pocket was randomized to TAS and the other to CHG. Both the TE and the pocket were irrigated in the respective solution. The primary outcome was the incidence of surgical site infections (SSI). Secondary outcomes were rates of mastectomy flap necrosis, hematoma, and seroma. Results Eighty-eight patients undergoing bilateral immediate breast reconstruction were enrolled. Demographic and operative characteristics were equivalent as each patient served as their own control. Between the TAS and CHG groups, there was no difference in the incidence of SSI (5 [4.5%] vs 7 [8.0%], p = 0.35), including minor infections (2 [2.3%] vs 1 [1.1%], p = 0.56), major infections (2 [2.3%] vs 6 [6.8%], p = 0.15), and those resulting in explantation (2 [2.3%] vs 5 [4.5%], p = 0.25). There was also no difference in necrosis, hematoma, or seroma formation. No patients who developed SSI had radiation. Conclusions This study does not demonstrate a statistically significant difference in SSI between TAS and CHG irrigation, though TAS approached statistical significance for lower rates of infectious complications.