Plasma for patients with primary type IV or V hyperlipoproteinemia inhibited [3H]thymidine incorporation by cultured mononuclear leukocytes. This previously unreported abnormality affected mononuclear leukocytes from patients with type IV or V hyperlipoproteinemia and from normal subjects. Patient cells incorporated [3H]thymidine normally when washed and incubated in medium containing normal plasma. Both spontaneous incorporation and stimulated incorporation in response to various mitogens and antigens were inhibited. The inhibitory effect was identified with the chylomicron and very low density lipoprotein fractions isolated from plasma and was concentration-dependent. Lectin used to stimulate cultured cells and [3H]thymidine used to measure responses were not bound to the lipoproteins in appreciable amounts. [3H]-Thymidine incorporation correlated well with morphologic evidence of lymphoproliferation. The mechanism of the inhibitory effect of type IV or V hyperlipoproteinemic plasma upon the response tested was not identified by may be related to interaction between lipoproteins and the cell membranes. We suggest that these lipoproteins may also interfere with the function of other cells.