Introduction: Infectious complications represent a major cause of morbidity and mortality in hairy cell leukemia (HCL) patients. Due to the immunosuppressive nature of the disease, these patients are frequently affected by opportunistic infections and rare pathogens. Furthermore, cytotoxic chemotherapy might lead to poor or even fatal outcomes in the setting of an active infection. Case Presentation: We report the case of a 62-year-old HCL patient who presented with recurrent fever episodes, pancytopenia, and mediastinal lymphadenopathy. A treatment decision against purine analogs and for rituximab mono was made as lymph node tissue revealed disseminated Mycobacterium kansasii infection. Together with specific antimycobacterial treatment, rituximab mono led to complete hematologic remission after 6 months without aggravating the accompanying infection. Conclusion: Here, we demonstrate successful treatment of HCL with rituximab in a patient with concomitant disseminated M. kansasii infection.