We report two cases of treatment failure in patients with osteoarticular infection associated with <i>Staphylococcus aureus</i> bacteremia and receiving daptomycin. Using a published population-pharmacokinetic model and daptomycin blood level in these patients, area under the curve (AUC) was calculated and compared to the pharmacological target. For the first patient, treated with 6 mg/kg every 48 hours due to acute renal failure and then every 24 hours, the AUC was 820 mg×h×L<sup>-1</sup>, with a minimal concentration of 23.5 mg/L confirming the right dose adjustment and the absence of underdosing. The methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) strain was still susceptible to daptomycin, but it was not sufficient to observe a favorable outcome. For the second patient, treated with 10 mg/kg/d, the steady state residual concentration was 10.4 mg/L, and the calculated AUC value was 550 mg×h×L<sup>-1</sup>. AUC/MIC values evolved during treatment to be under the cut-off for bactericidal effects (> 800 hours), and the <i>Staphylococcus aureus</i> (SA) strain became daptomycin resistant. This study highlights the inter-individual pharmacokinetic variation leading sometimes to drug underdosing. Drug monitoring should be encouraged in order to avoid treatment failure.