We have established a long-term culture system to study macrophages chronically infected with mycobacteria. Monocytes are infected with Bacillus Calmette-Guerin (BCG) and support exponential intracellular replication without profound perturbation of normal host cell function. We have used this system to investigate lymphokine-activated killer (LAK)-mediated cytolysis. We have found that interleukin 2 stimulation of peripheral blood lymphocytes generates a cytotoxic activity against human monocytes. A CD56- subpopulation of LAK cells specifically recognizes and lyses BCG-infected cells. Lysis of the host cell has no effect on parasite viability and results in the liberation of bacteria capable of infecting more cells.