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The long-term outcome and spectrum of disease of nontuberculous mycobacterial immune reconstitution syndrome have not been described.We report the findings of an observational study.Among 51 patients (43 with Mycobacterium avium complex [MAC] infection, 2 with Mycobacterium genavense infection, and 6 whose samples were smear positive but culture negative) from 1993-2004, the median follow-up period was 29 months. The incidence of nontuberculous mycobacterial immune reconstitution syndrome was 3.5% among patients initiating highly active antiretroviral therapy (HAART) with a baseline CD4+ cell count of <100 cells/μL. Three main clinical presentations were peripheral lymphadenitis (in 17 patients), pulmonary-thoracic disease (in 15 patients), and intra-abdominal disease (in 13 patients). Six other patients had cases that involved joint, spine, prostate, skin, soft tissue, and spontaneously resolving MAC bacteremia. Disease was usually localized. Median CD4+ cell counts before initiation of HAART and at diagnosis were 20 and 120 cells/μL, respectively, and the median reduction in human immunodeficiency virus (HIV) RNA load was 2.5 log10 copies/mL. Intra-abdominal disease was frequently preceded by disseminated MAC infection (in 62% of cases, compared with 6%-33% of cases for other groups; P =.003) and accounted for 16 (43%) of 36 hospitalizations (compared with 5%-35% for other groups; P =.008). The relapse rate was not higher among 10 patients who received no MAC therapy or received MAC therapy for ≤2 weeks. Prednisone was associated with clinical responses in 8 (89%) of 9 patients with evaluable cases. In total, 7 patients (14%) had 13 subsequent culture-positive MAC events (6 of which were cases of immune reconstitution syndrome, and 7 of which were cases of disseminated MAC infection). Ten patients (20%) died (2 of disseminated MAC infection, 5 of other opportunistic infections, and 3 of HIV-unrelated causes).Nontuberculous mycobacterial immune reconstitution syndrome has a wide range of clinical presentations and severity. The long-term prognosis is favorable for HAART-adherent patients. Intra-abdominal disease is associated with greater morbidity than is peripheral lymphadenitis. The role of antimycobacterial therapy is uncertain, given the self-limited course of most nonabdominal cases.