SWISS mice, edible frogs and goldfish i.p. injected with zymosan (Z groups) develop peritoneal inflammation connected with a massive intraperitoneal accumulation of leukocytes, which is significantly diminished in mice and fish (but not frogs) by supplementation of zymosan with morphine (ZM groups). In order to check the putative role of resident peritoneal macrophages in morphine-modulated zymosan-induced peritonitis, some animals were depleted of resident macrophages by repeated i.p. injections of clodronate-liposomes (CL) followed by Z or ZMinjection. In SWISS mice such CL-induced removal of Mac-3-positive cells (macrophages) resulted in an enhanced influx and prolonged accumulation of polymorphonuclear leukocytes (PMNs) in CL-Z and CL-ZM groups in comparison with their counterparts with intact macrophages. Nevertheless, supplementation of zymosan with morphine inhibited the early stages of peritonitis in CL-treated animals as it did in untreated mice. This indicates that intact peritoneal macrophages of SWISS mice are important for limiting PMN accumulation, perhaps mainly through the release of IL-10, but are not critical for the induction of anti-inflammatory effects of morphine during the early stages of peritonitis. Unexpectedly, macrophage depletion in CL-treated frogs and fish resulted in a lack of a typical peritonitis in both Z and ZM groups of these ectothermic animals.