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The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab has been shown to reduce the risk of SARS-CoV-2 infection in unvaccinated individuals during the Alpha (B.1.1.7) and Delta (B.1.617.2) waves. However, data on the efficacy and safety of tixagevimab/cilgavimab in vaccinated solid organ transplant recipients during the Omicron wave is limited. To address this, we conducted a retrospective cohort study comparing 222 solid organ transplant recipients (SOTRs) who received tixagevimab/cilgavimab for pre-exposure prophylaxis and 222 vaccine-matched solid organ transplant recipients who did not receive tixagevimab/cilgavimab. Breakthrough SARS-CoV-2 infections occurred in 11 (5%) of SOTRs who received tixagevimab/cilgavimab and in 32 (14%) of SOTRs in the control group (p .001). In the tixagevimab/cilgavimab group, SOTRs who received the 150-150 mg dose had a higher incidence of breakthrough infections compared to those who received the 300-300 mg dose (p = .025). Adverse events were uncommon, occurring in 4% of our cohort and most were mild. There was no significant change in serum creatinine or liver chemistries in kidney and liver transplant recipients, respectively. In conclusion, we found that tixagevimab/cilgavimab use is safe and associated with a lower risk of breakthrough SARS-CoV-2 infection in vaccinated solid organ transplant recipients during the Omicron wave.