Exogenous antigens are generally presented by Class II major histocompatibility (MHC) molecules. When administered with an adjuvant, however, they are capable of inducing a CD8⁺ T‐cell response where antigen recognition is associated with Class I MHC. Accordingly, immunization with soluble ovalbumin (OVA) alone does not activate CD8⁺ cytotoxic T cells (CTL) but when given in complete Freund's adjuvant (CFA), or in formulations of a number of novel adjuvants, an OVA‐specific CD8⁺ CTL response can be detected. We show in this report that immunization with soluble OVA mixed with heat‐killed Mycobacterium vaccae, but not with other common pathogenic and saprophytic mycobacteria, can activate OVA‐specific CD8⁺ CTL. An OVA‐specific CTL response is detected when mice are immunized by either the intraperitoneal or intranasal route and their spleen cells are re‐stimulated in vitro. Adjuvant activity of heat‐killed M. vaccae is present in M. vaccae culture filtrate, in soluble protein components of whole M. vaccae and in the 65 kDa heat‐shock protein (hsp) of M. vaccae. Mycobacterium vaccae has previously been shown to have no adverse side‐effects in humans. The current results suggest that M. vaccae may be useful as an adjuvant for vaccines and other immunotherapies where CD8⁺ CTL responses to exogenous proteins are crucial.