Pulmonary granulomatous inflammation was induced by the intratracheal injection of viable bacillus Calmette-Guerin (BCG) into genetically high granuloma responder (C57BL/6J and BALB/c) and low responder (CBA/J) mice with and without immunization by methylated bovine serum albumin in complete Freund's adjuvant. Significant migration inhibition factor (MIF) and interleukin 1 (IL 1) activities were detected in aqueous lung granuloma extracts prepared from high responder mice bearing BCG-induced granulomatous inflammation. Interleukin 2 activity was not detected. Very low MIF and IL 1 activities were detected in extracts from low responder mice. Furthermore, high responder, but not low responder, mice showed marked suppression of in vivo and in vitro manifestations of cell-mediated immunity to both specific and nonspecific antigens. In contrast, humoral antibody response was not affected significantly. The kinetics of anergy in granuloma-bearing mice correlated closely with the appearance of MIF and IL 1 activities in the lesions. Thus, genetically determined granuloma response to BCG and the expression of anergy in various strains of mice were well associated with in vivo release of MIF and IL 1. These results indicate that the genetic ability or inability to mount a granulomatous inflammatory response to BCG may extend to the capacity of cells within the lesions to generate soluble mediator(s) which is also responsible for anergy in granuloma-bearing mice.