Several small studies have indicated an impaired cell mediated immune response as a possible cause for the delayed elimination of the bacteria in Whipple's disease. A specific defect, however, has not been defined. We examined the expression of cell surface molecules and mitogenic responses of peripheral blood mononuclear cells in 27 patients with Whipple's disease at different disease stages by indirect immunofluorescence and by measurement of [3H]thymidine incorporation, respectively. E-rosette formation and cutaneous reaction to seven recall antigens were determined. Matched healthy donors served as controls. We found a significantly reduced number of cells expressing the complement receptor 3 alpha-chain (= CD11b) in all patients. In florid disease, the number of activated cells (in particular CD58 positive cells) was increased and CD4/CD8 ratios were diminished. Proliferation to phytohemagglutinin and to sheep red blood cells was reduced at all stages of the disease. Serum of control persons reversed this decreased responsiveness especially in patients with active disease. Skin reaction was hypoergic in all patients. Determination of CD58 positive cells increased in patients with active disease may be useful to define the activity of the disease and the duration necessary for treatment. Transient inhibiting serum activities may impair the CD2/CD58 interaction. The reduction of cells expressing CD11b, the decreased proliferation, and the cutaneous hypoergy indicate a persisting defect of cell mediated immunity in vivo and in vitro. These defects may contribute to the impaired ability of patients with Whipple's disease to eliminate bacteria.