BACKGROUND: In obese patients receiving intravenous (IV) acyclovir, conflicting data exist regarding the risk of acute kidney injury (AKI) with different weight-based dosing strategies: total body weight (TBW), adjusted body weight (AdjBW), and ideal body weight (IBW). OBJECTIVE: We aimed to compare the safety of the 3 dosing strategies in obese patients. METHODS: A retrospective cohort study including obese patients who received IV acyclovir during their inpatient admissions. Patients were categorized into TBW, AdjBW, or IBW groups based on the received doses. The primary outcome was the incidence of AKI. Other outcomes included the need for renal replacement therapy (RRT), neurotoxicity, length of stay (LOS), and in-hospital mortality. RESULTS: A total of 339 patients were included: 196 patients in TBW group, 86 patients in AdjBW group, and 57 patients in IBW group. The AKI developed in 17.3%, 11.6%, and 7% of TBW, AdjBW and IBW groups, respectively. After adjustment for confounders, reduced dosing (AdjBW or IBW) was associated with fewer AKI compared with TBW dosing (adjusted odds ratio (aOR) [95% CI] = 0.39 [0.19, 0.82]). Compared with TBW, IBW was associated with fewer AKI (aOR [95% CI] = 0.27 [0.08, 0.85]), but AdjBW was not (aOR [95% CI] = 0.48 [0.21, 1.09]). Median LOS was numerically longer with IBW but was not significantly different from other groups. The need for RRT, neurotoxicity, and mortality did not differ between groups. CONCLUSION AND RELEVANCE: In obese patients, either AdjBW or IBW dosing of IV acyclovir appears to be safer than TBW. The IBW dosing had the lowest odds of AKI among the 3 dosing strategies.