The present experiment was designed to investigate the mode of action of indomethacin, a prostaglandin synthesis inhibitor, as an antifertility agent, and to examine a possible effect of indomethacin administered during the normal peri-implantation period on the protein content and progesterone concentration in plasma and uterine fluid in pseudopregnant rabbits. The results showed that treatment with indomethacin significantly reduced the plasma progesterone concentrations, decreased progesterone concentrations in uterine flushing, significantly decreased the total plasma proteins, and particularly decreased albumin in the plasma and in the uterine flushings. Uteroglobin production by the rabbit uterus was not affected by this treatment. It is concluded that the antifertility effect of indomethacin at the time of implantation is exerted by reducing progesterone concentrations in plasma and uterine fluid, possibly affecting steroidogenesis, and by reducing the percentage of albumin in plasma and in uterine fluid, probably by increasing renal excretion of albumin. These effects of indomethacin provide an environment within the uterus that would not support embryo implantation and development.