Granulomatous lung disease was produced in strain 2 but not strain 13 guinea pigs by endotracheal injection of beryllium oxide (BeO), although isolated multinucleated giant cells containing crystalline material were found in lungs of both strains. Disease was also produced in (2 × 13) F1 hybrids, but of a milder form than in strain 2. In BeO-treated strain 2 and F1 animals, challenge with beryllium salts produced delayed hypersensitivity skin reactivity, and in vitro, enhanced tritiated thymidine uptake and lymphokine production by lymph node cells. No evidence was found for involvement of humoral immunity in the disease. Responses were not seen in BeO-treated strain 13 guinea pigs, and immunization of animals with BeO in complete Freund’s adjuvant produced similar immunologic findings. These data emphasize the involvement of genetically determined cellular immune mechanisms in beryllium lung disease.