The tissue reactions of non-tumor-bearing F1 (DBA/2 X C57B16) mice to i.v. and s.c. injected BCG were studied in animals sacrificed at planned intervals following the injection. No appreciable changes were observed prior to day 6, when the thymic cortex and medulla began to show hyperplasia of epithelial cells; many of them had PAS positive cytoplasm and some of these cells were contiguous with the walls of small blood vessels and large cystic spaces containing PAS-positive secretions. The thymic cortical lymphocytes showed, on day 6, a pronounced pyroninophilia and increased mitotic activity without increase in thymic weight. These changes were considerably more striking in the i.v. than in the s.c. injected animals. On the same day a pronounced multifocal lymphocytic infiltration involving the red pulp and the parafollicular and periarteriolar zones of the spleen were observed. It was more pronounced in the i.v. than in the s.c. injected animals. The thymic changes were seen only in animals killed on day 6 and day 10, but were no longer observed on day 14. Beginning with day 14 a pronounced histiocytic granulomatous reaction was observed in the liver. On day 18, this granulomatous reaction was also seen in the spleen, lymph nodes, and lungs of i.v. injected animals. It persisted until day 45. In the s.c. injected animals histiocytic granulomas were seen only at the site of injection and in the regional lymph nodes.