We searched PubMed and Cochrane databases to review the available evidence regarding the use of linezolid in combination with other drugs for the treatment of patients with mycobacterial infection. Case reports, case series, prospective and retrospective studies, and randomized controlled trials were eligible for inclusion in our systematic review if they evaluated the effectiveness and safety of linezolid for the treatment of patients with mycobacterial infection. Four studies were available, including 24 cases of patients with [corrected] mycobacterial infection. Cure of the infection, defined as sterilization of mycobacterial cultures or resolution of symptoms, was achieved in 15 of the 24 cases (62.5%) with mycobacterial infection (mainly tuberculosis). Sterile cultures were also achieved in three other cases, although the patients had stopped linezolid (two because of optic neuropathy and one due to economic reasons; all three continued on second-line therapy). On the other hand, serious adverse events were observed in the majority of patients with mycobacterial infection treated with combinations that included linezolid (18/24, 75%). Neuropathy (peripheral and/or optic) and anemia were reported in 11/24 (45.8%) and 10/24 (41.7%) cases, respectively. Although the limited evidence suggests that linezolid may be considered as a second-line agent for mycobacterial infections, any treatment with linezolid should be weighed against the risks associated with its long-term use.