<b><i>Background:</i></b> The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established. <b><i>Methods:</i></b> Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days. <b><i>Results:</i></b> At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 ± 356.6 mg·h/l, and the maximum concentration (Cmax) was 66.9 ±25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R² = 0.91, p < 0.001, and R² = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R² = 0.7, p = 0.009). <b><i>Conclusion:</i></b> No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT.