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Trimethoprim/sulfamethoxazole is the first-line agent for oral eradication therapy for melioidosis but has been associated with toxicity in this context. This study aimed to quantify adverse drug reactions (ADRs) to trimethoprim/sulfamethoxazole when used for treatment of melioidosis, and assess risk factors for ADR development. A retrospective review of antimicrobial associated ADRs was performed in all patients treated for melioidosis in the Northern Territory of Australia from January 2017-September 2022. Over this time, 268 treatment episodes from 256 individuals were included. The frequency of clinician-attributed ADRs to trimethoprim/sulfamethoxazole (51% of exposed) was higher than for other antimicrobials used (ceftazidime 12%, meropenem 8%, and doxycycline 12% of those exposed; P < 0.0001). 44% of those treated with trimethoprim/sulfamethoxazole required drug cessation or dose reduction and 5 individuals (2%) had a severe cutaneous adverse reaction, with one fatality. Acute kidney injury was the most frequent ADR (25% of those exposed), with age and pre-existing renal disease independently associated with its development. Here we report very high rates of ADRs attributed to trimethoprim/sulfamethoxazole resulting in frequent discontinuation of this drug as part of oral eradication therapy for melioidosis. Further work is needed to balance the necessity and toxicity of this drug in this clinical context.