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Background: Trimethoprim-­sulfamethoxazole (TMP-­SMX) is the drug of choice for Pneumocystis jirovecii pneumonia (PJP) prophylaxis and has activity against other opportunistic infections (OIs) after solid organ transplant (SOT). We aimed to describe the incidence, reasons for and outcomes of use of alternative prophylactic agents (APAs) across SOT programs in our high volume centers. Methods: Solid organ transplant recipients (SOTRs) at our centers from 1/2015-­ 12/2016 were identified. Pharmacy records identified APA (pentamidine, atovaquone, or dapsone) use within 1 year. Records were reviewed for allergies, laboratory values at APA initiation, diagnostic tests for TMP-­SMX-­preventable OIs, and APA side effects. Results: An APA was initiated in 105/1173 (8.9%) SOTRs. Of these, 51 (48.6%) were because of sulfonamide allergy recorded pre-­SOT, mostly rash/hives (58.8%). The remaining 54 (51.4%) had TMP-­SMX discontinued post-­SOT, mostly for neutropenia (48%) and renal effects (34%). Differences occurred across programs, with kidney transplant never stopping TMP-­SMX for renal issues. Of those changed to APAs post-­transplant, 19 (35%) were later successfully re-c­hallenged with TMP-­SMX. With thresholds in mind, 67 (64%) received an APA unnecessarily, accounting for up to $100 000/y excess cost. Potential TMP-­SMX-­preventable OIs occurred in 7 (5 Nocardia; 2 PJP). APA side effects occurred in 14/105 (13.3%). Conclusions: Use of APAs for PJP prophylaxis after SOT is less than previously reported but often unwarranted. Such decisions require scrutiny to avoid TMP-­SMX-­ preventable OIs, cost and important APA side effects. Use of reasonable thresholds for cessation of TMP-­SMX and data-­driven approaches to re-­challenge would substantially reduce APA use.