Quartz and trehalose 6,6'-dimycolate (TDM) both potentiate tuberculosis and have toxicities that depend on surface crystalline structures. Investigations were undertaken to determine if TDM can kill macrophages and produce hemolysis in a fashion similar to that of quartz and if quartz can induce granulomas similar to those induced by TDM. Trehalose 6,6'-dimycolate was spread as a molecular monolayer on the surface of tissue culture dishes adjacent to areas of uncoated plastic for comparison. Murine peritoneal macrophages were killed within hours by contact with the TDM monolayer, while those on adjacent areas of uncoated plastic remained viable and spread normally. The membranes of erythrocytes were also damaged by contact with the monolayer of TDM. This damage was inhibited by poly-2-vinyl-pyridine-N-oxide, an inhibitor of hydrogen bonding that blocks quartz induced hemolysis. These data suggest that TDM damages membranes via an adhesive mechanism similar to that of quartz. Furthermore, injections of quartz particles into mice induce acute granulomatous reactions similar to those induced by TDM. These data indicate that TDM and quartz have certain similarities in their mechanisms of action and that these similarities may be of importance in the pathogenesis of tuberculosis.