Background <p><i>Mycobacterium avium</i> complex pulmonary disease (MAC-PD) is a refractory infectious disease, with a low success rate of the antimicrobial therapy. T cells and macrophages play a critical role in regulating the mechanism of immunity against mycobacterial infections. Although T cell dysfunction may be associated with treatment failure in MAC-PD, supporting evidence is scarce. This study aimed to elucidate the immunological characteristics of patients with refractory MAC-PD, focusing on immunosuppression and T cell exhaustion.</p> Methods <p>Patients with MAC-PD who received standard antimicrobial therapy for at least 12&#xa0;months were enrolled and classified into treatment success or failure groups. Flow cytometry was used to investigate CD4⁺ and CD8⁺ T cell characteristics in peripheral blood mononuclear cells.</p> Results <p>This study involved 41 patients, including 21 and 20 in the treatment success and failure groups, respectively. Patients with MAC-PD had higher expression of co-inhibitory molecules, including PD-1 and TIM-3, as well as CD160, LAG-3, and 2B4, on CD4⁺ and CD8⁺ T cells than healthy controls. However, no differences in expression were observed between the treatment success and failure groups for most activation, co-stimulatory, and co-inhibitory molecules and transcription factors. Furthermore, no difference in effector cytokine production (IL-2, TNF, and IFN-γ) in CD4⁺ and CD8⁺ T cells was observed between the groups. However, patients with MAC-PD with low IL-2-producing CD8⁺ T cells had a significantly longer disease duration than those with moderate and high IL-2-producing status (138.3 vs. 42.7&#xa0;months). CD8⁺ T cells from patients with MAC-PD with low IL-2 production and prolonged disease duration tended to express higher 2B4 and lower CD28 levels.</p> Conclusions <p>The effector functions of CD4⁺ and CD8⁺ T cells are not lost during treatment failure. However, low CD8⁺ T cell IL-2 production was significantly associated with longer disease duration. High 2B4 and low CD28 expression on CD8⁺ T cells may represent potential markers of T cell dysfunction. Such patients may serve as suitable targets for future host-directed therapies.</p> Trial registration <p>This study was registered with the University Hospital Medical Information Network of Japan (registration number: UMIN000043426, registration date: March 1, 2021).</p>