Background In the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs). Methods Plasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated. Results A total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%. Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for two oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for one antibiotic. One patient did not reach target for any of the two antibiotics. Conclusion For the individual orally administered antibiotic, the majority of patients reached the target level. Patients with sub-target levels were compensated by the administration of two different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis.