We have studied synthesis of apolipoprotein E (apo-E) and apo-E mRNA in cultures of peripheral blood human monocyte macrophages (M-M cultures) obtained from a patient with familial apolipoprotein E deficiency. We have found that the M-M cultures of the apo-E-deficient patients contained two apo-E mRNA species with slightly different molecular weight as compared to normal apo-E mRNA. The apo-E mRNA concentration of the apo-E-deficient cultures was approximately 50-fold reduced as compared to the normal cultures, whereas the actin mRNA concentrations were identical in both M-M cultures. Genomic blotting analysis using a full-length apo-E cDNA clone as hybridization probe did not show gross differences between the restriction patterns of the DNA obtained from the apo-E-deficient patient and two normal controls. When normal M-M cultures were grown in media containing [35S]methionine they synthesized and secreted apo-E into the culture media. In contrast we could not detect any intracellular or extracellular apo-E in the patient's M-M cultures grown under identical conditions. These observations are consistent with the hypothesis that familial apo-E deficiency results from structural apo-E gene mutation(s). The putative mutation(s) affect either the transcription of the apo-E gene or the processing of the primary apo-E mRNA transcript. These abnormalities are associated with low levels of synthesis of aberrant apo-E mRNA forms which are either very unstable or cannot be translated into protein.