Introduction: Prosthetic joint infection (PJI) is a serious complication of arthroplasty, associated with significant morbidity and therapeutic challenges, particularly due to biofilm formation and the emergence of multidrug-resistant (MDR) bacteria. In Morocco, where osteoarticular trauma and resistant nosocomial pathogens are frequent, a local assessment of PJIs is warranted. The objectives of our study are to determine the frequency of infections in prostheses, specify the epidemiology and resistance profile of isolated strains to antibiotics. Methods: This is a retrospective study conducted in the bacteriology laboratory of the Mohammed V Military Teaching Hospital in Rabat over a 4-year period (2015–2018), involving 572 arthroplasties. Samples were processed using standard microbiological techniques, and antimicrobial susceptibility testing was performed by the disk diffusion method and interpreted according to CA-SFM/EUCAST guidelines. Results: Out of 53 samples received, 37 (69.8%) were culture-positive. Twenty-four cases of PJIs were confirmed, representing an infection rate of 4.19%, predominantly affecting hip prostheses (3.49%). Delayed infections (3–24 months post-surgery) were the most frequent (87.5%). Gram-positive cocci accounted for 59.5% of isolates, followed by Enterobacterales at 31.7%. Staphylococcus aureus was 100% methicillin-susceptible, while 26% of coagulase-negative staphylococci were methicillin-resistant. Resistance rates among Enterobacterales were 32% for cefotaxime and 4% for imipenem. Conclusion: PJIs represent a major issue in our setting, with a predominance of staphylococci and an alarming emergence of multidrug-resistant Gram-negative bacilli. These findings highlight the need for rigorous diagnostic protocols, strengthened preventive measures, and antibiotic policies tailored to the local microbiological ecology.