OBJECTIVE To examine the effect of Ethiodol oil-soluble contrast medium and Sinografin aqueous-soluble contrast medium on macrophage function. After the observation that Ethiodol alters macrophage phagocytosis and adherence, we sought to determine the mechanism of action by which oil-soluble contrast medium alters the macrophage membrane. METHODS The P388D1 cell line was used as a consistent source of macrophages for all experiments. The uptake of 3H-labeled candida albicans was determined in macrophages exposed to 1:100, 1:400, or 1:800 dilutions of Ethiodol, Sinografin (S.R. Squibb, Princeton, NJ) or untreated media. To evaluate the macrophage adherence, 51Cr-labeled macrophages were exposed to the same dilutions of the contrast media. Specific membrane properties, Fc receptor levels, electronegativity, and microviscosity were assessed by flow cytometry after exposure to 1:100 dilutions of Ethiodol or Sinografin. RESULTS Macrophage phagocytosis was decreased upon exposure to 1:100 and 1:400 dilutions of Ethiodol contrast medium, whereas adherence was reduced at the 1:100 dilution of Ethiodol. There was no effect of any dilution of Sinografin. There was a reduction in membrane electronegativity and microviscosity, but not Fc receptor levels, after exposure to a 1:100 dilution of Ethiodol. CONCLUSIONS This study establishes a decrease in macrophage phagocytosis and adherence after exposure to Ethiodol oil-soluble contrast medium. We established that this alteration in membrane function is caused by a reduction of membrane negative surface charge and microviscosity. This may suggest a mechanism of action for the therapeutic effect of oil-contrast hysterosalpingograms in women with unexplained infertility.