Prosthetic joint infection (PJI) occurs with significant morbidity and health care expenditure. Transplant recipients on immunosuppressive medications are at increased risk for infections caused by less common organisms at unusual sites. Here we report a case of isolated PJI with Mycobacterium avium complex (MAC) in an immunosuppressed failed kidney transplant recipient and review the literature on this unique infection. We discuss the likely pathogenesis of PJI with MAC including the role of biofilm formation by non-tuberculous mycobacteria. The possible role of cytokine milieu alteration by immunosuppressive therapy, particularly the reduction in interferon-gamma levels, as a predisposing factor for non-tuberculous mycobacterial infections in transplant recipients is explored. Lastly, we review the role of immune cell function assay in predicting the susceptibility to infection in our patient specifically and in solid organ transplant recipients in general.