Macrophage activation is thought to be mediated via a number of T-lymphocyte products, including gamma interferon (IFN-gamma). However, our studies indicate that IFN-gamma acts as a regulator molecule rather than solely as an activator. This depends upon the status of the macrophage. IFN-gamma treatment of resting macrophages and those activated or elicited by sodium caseinate, lipopolysaccharide, or Mycobacterium bovis BCG did not result in activation, as measured by hydrogen peroxide production; however, when thioglycolate was used as an eliciting agent, incubation with IFN-gamma resulted in a dramatic increase in hydrogen peroxide production compared with that by untreated controls.