BACKGROUND: Intraoperative expansion with air, as compared with saline, has been associated with fewer first-stage complications in 2-stage expander-implant breast reconstruction. However, longitudinal reconstructive outcomes, postoperative medication use indicating pain or discomfort, as well as patient-reported outcome measures after intraoperative air versus saline fill have not yet been investigated. METHODS: This is a retrospective cohort investigation of 69 patients who underwent 2-stage expander-implant prepectoral breast reconstruction with acellular dermal matrix in 2017 and 2018. Patients underwent intraoperative tissue expander (TE) fill with air or saline during stage 1 of reconstruction and underwent expander-implant exchange in stage 2. Air versus saline cohorts were compared with regards to time to definitive reconstruction and postoperative pain/opioid use. RESULTS: Of the 69 patients studied, 47 (68.1%) had tissue expanders filled with air and 22 (31.9%) filled with saline. In multivariable regression analysis, air-filled TEs were associated with significantly lower odds of requiring an opioid prescription refill (adjusted odds ratio [aOR] = 0.27; = .009) and breast pain (aOR = 0.10; < .001). The use of air instead of saline TEs also had no adverse impact on the length of time or number of office visits between stages. CONCLUSIONS: Intraoperative air versus saline TE fill appears to impact longitudinal reconstructive outcomes in expander-implant based reconstruction. Our results demonstrated that air-filled TEs were associated with significantly lower odds of opioid refills and breast pain. Our study also indicates that timing and office visits between stages do not appear to be affected by TE fill medium.