Osteomyelitis remains one of the most intractable diseases. The nature of the pathogen and its resistance to antibiotics significantly affect the outcome and cost of treatment.The aim of the study: to analyze the dynamics of the spectrum and antibiotic resistance of the leading pathogens of orthopedic infection for the period 2012– 2017.Material and methods. The structure of pathogens isolated from the focus of infection from 2774 patients with periprosthetic infection and chronic osteomyelitis was retrospectively analyzed. Antibiotic resistance of the leading pathogens that occupied more than 4% in the species structure was studied. Comparative analysis of changes in the spectrum of pathogens and antibiotic resistance was carried out for the periods 2012-2013, 2014–2015 and 2016-2017. Epidemiological analysis was performed in the program „microbiological monitoring system” Microbe-2. Statistical processing of the obtained data was carried out using the Z-criterion.Results.From 2774 patients with orthopedic infection have been isolated 4359 strains, in the structure of which about 73.5% were occupied by S. aureus, S. epidermidis, E. faecalis, E. faecium, P. aeruginosa, Acinetobacter sp. representatives of the family Enterobacteriacea. In 27% of the cases, microorganisms of other species were identified. Microbial associations were identified in 19.4% of cases. In the structure of the leading Gram(+) pathogens, a significant decrease in the incidence of S. aureus was detected, while the share of S. epidermidis increased significantly. Among the leading Gram(-) microorganisms, a significant increase in the proportion of representatives of the fam. Enterobacteriacea was found, against the background of a decrease in the share of Acinetobacter sp. and P. aeruginosa. The level of resistance of MSSA to the studied antibiotics ranged from 0.1 to 8.8%, for MSSE the spread was from 1.9 to 16.7%. Negative dynamics of growth of resistance of non-fermenting bacteria is established. The strains of Acinetobacter sp. demonstrated greater resistance to tested antibiotics in comparison with P. aeruginosa.Conclusion.An increase in the role of S. epidermidis and K. pneumoniae in the etiology of orthopedic infection was established. The revealed increase in the resistance of microbial pathogens to most tested and used antibiotics should be taken into account in the appointment of empirical antibiotic therapy. The extremely high frequency of resistance of gram-negative bacteria to cephalosporins and fluoroquinolones excludes the possibility of their empirical use, which requires the management of carbapenems in the starting treatment regimens. High resistance to fluoroquinolones limits the ability of oral antibiotic therapy in patients with periprosthetic infection.