Sodium salicylate, disodium ethylenediaminetetraacetic acid (EDTA) and polyoxyethylene-23-lauryl ether (POE) significantly enhanced the absorption of cefoxitin from the rectum but with the following differences. The effectiveness of salicylate or EDTA was enhanced by sodium chloride, whereas the activity of POE was not. Although the ratios of plasma cefoxitin peak values to cefoxitin dose were constant with POE or EDTA, the peak to dose ratios with salicylate decreased with increasing cefoxitin concentration. Phlorizin and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited the effectiveness of salicylate, but did not influence the adjuvant action of either POE or EDTA. Although treatment with salicylate resulted in slightly less protein release than treatment with NaCl, both POE and EDTA increased the release of protein from the rectal mucosa. It appears that the effects of salicylate occur at the protein fraction of the rectal mucosa through a saturable process whereas the adjuvant action of POE and EDTA appears to involve some irreversible disruption of the membrane.