We have previously shown that peripheral blood lymphocytes from patients with chronic lymphocytic leukemia (CLL) express increased amounts of the minor p35 form of class II invariant chain (Ii) relative to the major p33 form. In this report we demonstrate in Western blots that in CLL lymphocytes, but not in normal or Epstein-Barr virus-transformed normal lymphocytes, p35 and p33 Ii form sodium dodecyl sulfate (SDS)-resistant complexes with class II alpha and beta chains and that these complexes form an abnormally large proportion of the total class II molecules. Others have shown that stable SDS-resistant alpha-beta complexes are only formed upon binding of exogenous antigenic peptides for presentation at the cell surface. Large amounts of p35 Ii remaining in the endoplasmic reticulum and capable of forming stable complexes with alpha and beta chains could compete with endogenous antigenic peptides for available class II peptide binding sites. The presentation of endogenous tumor antigens would thus be prevented, leading to the escape of the CLL clone from immunological surveillance.