Stress-induced proteins (or heat shock proteins (HSPs)) of 96 kDa size (gp96) have been shown previously to elicit specific immunity to tumors from which they are isolated. In this report, we show that in contrast to Meth A-derived gp96, gp96 preparations derived from normal tissues did not elicit immunity to Meth A sarcoma at any dose tested. Further, in light of recent studies showing that other major cellular HSPs hsp90 and hsp70 also elicit tumor-specific immunity, we have compared the relative immunogenicities of gp96, hsp90, and hsp70 derived from the Meth A sarcoma. The proteins gp96 and hsp70 were observed to be highly and equally immunogenic, whereas the immunogenicity of hsp90 was approximately 10% of that of gp96 or hsp70. It is suggested that the poor immunogenicity of hsp90 results from its lack of a measurable ATPase activity, which has been implicated in the ability of HSPs to transfer peptide to acceptor molecules. This is the first study that documents the lack of immunogenicity of gp96 preparations derived from normal tissues and compares the immunogenicity of each of the three major cellular HSPs in one tumor system.