Background: A particular ability of the Staphylococcus aureus clonal complex 398 (CC398) to cause bone and joint infections (BJI) remains questionable, since some studies have described high prevalence of MSSA CC398 in prosthetic joint infection (PJI) and diabetic foot ostemolyelitis (DFO). Here, we described the long-term epidemiology of CC398 among S. aureus isolated from BJI and identified risk factors associated with CC398. Methods: We included all bone and joint samples with S. aureus-positive culture in our university hospital between January 2010 and December 2017. Logistic regression was used for univariate and multivariate analysis. Results: We identified 124 CC398 isolates among the 958 BJI-associated S. aureus. The proportion of CC398 among S. aureus increased steadily from 4% in 2010 to 26% in 2017. Only 4 isolates of CC398 were resistant to methicillin. The distribution of BJI types due to CC398 and non CC398 isolates was similar. In multivariate analysis, age (p = 0.034, OR = 3.9), McCabe score (p = 0.005, OR = 5) and inoculation mechanism (p = 0.020, OR = 3.7) were associated with PJI-related CC398. The year of infection (p < 0.001, OR = 1.6), Charlson’s score (p = 0.001, OR = 1.5) and grade 4 (severe) of the International Working Group of the Diabetic Foot classification (p < 0.001, OR = 8.5) were associated with DFO-related CC398. Conclusion: We highlighted here the emergence and spread of CC398-MSSA in BJI. Patients with comorbidities are at high risk of CC398 MSSA PJI and DFO. The spread of CC398 in the community and hospital settings remains unclear and further epidemiological studies are needed to identify the determinants of its success.