We have previously shown that heat-killed bacillus Calmette-Guérin (BCG) injected into the brain parenchyma becomes sequestered behind the blood-brain barrier for months, apparently unrecognised by the immune system (Matyszak and Perry, 1995, 1996a,b). In this paper we have studied T-cell and antibody responses to purified protein derivative (PPD) at different times after intracranial injection of BCG or after the same dose of BCG was injected intradermally. We detected no antibody to PPD in the sera of animals which received intracranial injection, although there was a clear antibody response in the sera of animals injected intradermally, as shown using immunoblot analysis. The skin contact sensitivity to PPD was robust in animals which had received a previous intradermal injection of BCG. 72 h after a PPD injection, the injected site showed many MHC class II + macrophages and T-cells. However, the response in skin following PPD challenge, in animals injected intracranially (i.c.), was comparable with that of naive animals which had received no previous BCG challenge. The skin lesions in animals injected i.c. and in naive animals, were characterised by a small number of MHC class II + cells and rare T-cells. T-cell responses were also studied in an in vitro proliferation assay. The proliferative response was measured for cells isolated from the cervical lymph nodes and the spleen. Cells purified from the spleen and the cervical lymph nodes of animals injected with BCG i.c. showed no specific proliferative response to PPD. The response was comparable to that found in naive, uninjected animals. However, spleen and cervical lymph node cells from animals injected intradermally with BCG showed a significant proliferative response to PPD. These results show that a dose of bacteria injected into the brain parenchyma fails to prime the immune system even though the same dose injected subcutaneously will do so. This response to bacteria in the CNS differs from that previously reported for soluble proteins.