Abstract Introduction/Objective Mycobacterium chelonae and Mycobacterium abscessus are rapidly growing non-tuberculous mycobacterium found in soil and water, and represent rare causes of skin and soft tissue infection. Treatment typically involves an extended course of antimicrobial therapy and occasionally surgical debridement. Previous reports have described a distinctive pattern of suppurative granulomatous inflammation with microcystic changes in skin biopsies; however, the morphologic changes of M. chelonae-abscessus complex as a cause of osteomyelitis have not been well-documented in the literature. Methods/Case Report We searched our database from 2013 to 2024 for bone samples diagnosed as granulomatous inflammation in which M. chelonae or M. abscessus were identified on concurrent microbiology studies. Patient demographics, risk factors for infection, and treatment data were collected. Results (if a Case Study enter NA) Three patients with culture- or PCR-confirmed M. chelonae (2) or M. abscessus (1) were identified. All infections involved bones of the distal extremities. Patients were 57 years and older with risk factors for infection that included: diabetes (1), intravenous drug use (1), and long-term immunosuppressive therapy (1). All patients presented with osteomyelitis refractory to antibiotic therapy for which bone biopsy, bone resection, or amputation was performed. All cases showed suppurative granulomatous inflammation with microcystic changes. Cystic spaces were markedly enriched for acid-fast bacilli on Fite and/or Ziehl-Neelsen stains. In two patients, the antimicrobial regimen was changed as a result of the pathologic findings and microbiologic testing that provided additional information about speciation and susceptibilities. Conclusion Suppurative granulomatous inflammation has a broad differential that includes blastomycosis, sporotrichosis, cat scratch disease, non-tuberculous mycobacterial infection, and granulomatosis with polyangiitis, for which there are substantial treatment differences. When this pattern of microcystic suppurative granulomatous inflammation is encountered, it is important to perform special stains for acid-fast bacilli, particularly when seen in distal extremity lesions from patients with infections that are refractory to empiric antibiotic therapy.