Purpose <p>Obese patients treated with daptomycin at 4&#xa0;mg/kg have a 30% increased drug exposure, potentially raising the risk of adverse events (AEs) like rhabdomyolysis. Given limited data on the safety of higher doses (10&#xa0;mg/kg) in this population, this study aimed to assess the safety of high-dose daptomycin in obese patients and to identify potential AEs risk factors.</p> Methods <p>This multicenter, retrospective observational study was conducted from June 2021 to May 2022 using medical records. Patients with a BMI &gt; 30&#xa0;kg/m² were classified as obese. AEs assessed included: CK elevation (&gt; 5x upper limit of normal), severe elevation (&gt; 10x upper limit), eosinophilic pneumonia, and elevated liver enzymes. Both univariate and multivariate analyses were conducted.</p> Results <p>A total of 1 303 patients were included: 970 non-obese and 333 Ob patients. These patients received an average daptomycin dose of 9.9&#xa0;mg/kg based on actual body weight for an average treatment duration of 8.27 days. One-third of the patients had CK monitoring. AEs rates were 3.5% for the n-Ob group vs. 8.7% in the Ob group (<i>p</i> &lt; 0.01). Ob patients had significantly higher CK levels (n-Ob, 9.5%; Ob, 20.3%; <i>p</i> = 0.001), and severe elevation (n-Ob, 5.2%; Ob, 10.9%; <i>p</i> = 0.03). Factors increasing AE risk included obesity, concomitant prescriptions of drugs with risk of rhabdomyolysis, eGFR 30–60 mL/min, and daptomycin duration (OR = 2.42; 4.34; 2.03 and 1.05, respectively, <i>p</i> &lt; 0.001). On the opposite, consultation with an infectious disease specialist reduced risk (OR = 0.52, <i>p</i> = 0.024).</p> Conclusion <p>This study highlights that obese patient has a significantly increased risk of AEs with high dose of daptomycin compared to non-obese patients. Adjusted body weight dosing may be considered to reduce AEs risk.</p>