Following treatment of a human B cell lymphoma with an anti-idiotype antibody, a subpopulation of tumor cells remained that had lost the tumor-specific heavy chain idiotypic determinant. Nucleotide sequence analyses of eight independent heavy chain variable region isolates showed extensive point mutations, so that no two sequences were identical. Comparison of pretreatment and posttreatment sequences implicated an amino acid in CDR2 as being involved in the idiotypic determinant. Apparently the malignant B cells escaped the therapeutic effects of the anti-idiotype antibody through an ongoing process of somatic mutation in their immunoglobulin genes. Non-random clustering of amino acid replacements in CDR2 suggested that growth of the tumor may have been influenced by endogenous selective forces interacting with the tumor cell-surface immunoglobulin.