Although multiple myeloma is a disease of plasma cells, abnormalities have been detected in both B and T lymphocytes in peripheral blood. Although multiple myeloma patients are deficient in surface Ig (sIg)- positive B lymphocytes, analysis of lymphocytes present in blood indicates an abnormally large pool of circulating pre-B cells. These pre-B cells express BA-1, do not bear sIg, and contain cytoplasmic mu chains. High numbers of pre-B cells occur in 88% of individuals with frank myeloma and in 44% of individuals with monoclonal gammopathy of undetermined significance. Pre-B cells bearing BA-1 differ between patients in their expression of HLA-DR and receptors for peanut agglutinin (PNA). Those pre-B cells in myeloma patients are either BA- 1+ PNA- HLA-DR+ (54% of patients) or BA-1+ PNA+ HLA-DR- (30% of patients), or have a mixture of phenotypes (14% of patients). Pre-B cells of the PNA- phenotype are almost always HLA-DR+, and PNA+ pre-B cells are HLA-DR-. Within the same patient, the pre-B cell population varies by both quantitative and qualitative definitions. The number of pre-B cells may increase 460-fold and temporal shifts of surface phenotype from BA-1+ PNA- to BA-1+ PNA+ or vice versa have been detected. These observations indicate an abnormality in the B lymphocyte differentiation pathway leading to pre-B cells in the periphery that vary in number and cell surface phenotype, and that are unable to express sIg.