Background: Hairy cell leukemia (HCL) particularly predisposes to mycobacterial infection due to a number of different reasons. Moreover, HCL clinical presentation may result atypical because of uncommon anatomic involvement and unusual systemic disorders. Case presentation: 59-year-old male, a heavy smoker, with a history of high fever associated with dyspnea and fatigue. Examinations showed mild anemia, leukopenia and thrombocytopenia. Imaging revealed pleural effusion associated with reticulonodular infiltrate with tree-in-bud sign. Different test on pleural effusion and on pleural biopsy resulted positive for both Mycobacterium tuberculosis and Non-tubercular mycobacteria (Mycobacterium chelonae). Soon after the start of the anti-mycobacterial treatment, the therapy was suspended due to the appearance of a diffuse cutaneous maculopapular exanthema associated with mild dyspnea. Skin biopsy showed a lymph-granulocytic vasculitis. Bone marrow biopsy followed by flow cytometry resulted positive for hairy cell leukemia. The administration of the appropriate chemotherapy for HCL and the reintroduction of antimycobacterial therapy brought to a prompt remission of fever, dyspnea and skin rash with improvement of laboratory parameters. Discussion: This case is unusual and challenging because of the rare coexistence of HCL, MTB and NTM, the mycobacterial infections preceding instead of following the hematological disease and the uncommon presentation of HCL as a cutaneous inflammatory vasculitis