Objectives: Data on clinical and biological tolerance of tedizolid (TZD) prolonged therapy are lacking. Methods: We conducted a prospective multicentre study including patients with prosthetic joint infections (PJIs) who were treated for at least 6 weeks but not more than 12 weeks. Results: Thirty-three adult patients of mean age 73.3 ± 10.5 years, with PJI including hip (n = 19), knee (n = 13) and shoulder (n = 1) were included. All patients were operated, with retention of the infected implants and one/two stage-replacements in 11 (33.3%) and 17/5 (51.5%/15.2%), respectively. Staphylococci and enterococci were the most prevalent bacteria identified. The mean duration of TZD therapy was 8.0 ± 3.27 weeks (6–12). TZD was associated with another antibiotic in 18 patients (54.5%), including rifampicin in 16 cases (48.5). Six patients (18.2%) had to stop TZD therapy prematurely because of intolerance which was potentially attributable to TZD (n = 2), early failure of PJI treatment (n = 2) or severe anaemia due to bleeding (n = 2). Regarding compliance with TZD therapy, no cases of two or more omissions of medication intake were recorded during the whole TZD treatment duration. Conclusions: These results suggest good compliance and a favourable safety profile of TZD, providing evidence of the potential benefit of the use of this agent for the antibiotic treatment of PJIs.