There has been a global increase in the incidence of multidrug‐resistant pulmonary tuberculosis (TB). As there are no previous reports of immune function in HIV patients with multidrug‐resistant pulmonary TB, a comprehensive assessment of cellular immunity in this setting was undertaken. This involved a prospective, case‐controlled study which included five patients with active multidrug‐resistant pulmonary TB and five matched controls with active non‐resistant infection, and documented the changes in immune parameters which occurred upon clinical resolution. Patients with multidrug‐resistant TB had significantly lower fresh natural killer (NK) cell activity than matched controls with non‐resistant pulmonary TB (P < 0.05). This was a specific abnormality, as there were no significant differences in antigen‐specific cytotoxicity or lymphocyte proliferation in the case‐controlled study. Follow‐up assessment of the patients with multidrug‐resistant infections indicated that clinical improvement correlated with a moderate increase in NK cell activity. Impaired NK cell function may be involved in the pathogenesis of multidrug‐resistant TB.