To determine the main mediators for mouse anaphylactic shock, the suppression of active anaphylactic shock by cyproheptadine, an antagonist of histamine/serotonin, and CV-6209, an antagonist of platelet-activating factor (PAF), was systematically evaluated using various mouse strains. The suppression was quite heterogeneic depending on the mouse strain and method for sensitization. When sensitization was done with bovine serum albumin (BSA) plus Bordetella pertussis organisms, anaphylactic shock in C57BL/6N mice was suppressed by cyproheptadine but not by CV-6209. In contrast, shock in C3H/HeN and WBB6F1-W/W^V mice was suppressed by CV-6209 but not by cyproheptadine. Shock in BALB/c mice was suppressed by both agents but that in WBB6F1-+/+ mice was not at all by either one. DS and BDF1 mice showed differences due to the length of the sensitization period; shock was not suppressed by cyproheptadine with a shorter sensitization (9 to 11 days) but clearly suppressed with prolonged sensitization of 14 to 15 days. Shock in DS, WBB6F1-+/+ and BDF1 mice, which was not suppressed by either agent alone, was strongly suppressed by the combination of the two agents. In animals which had been sensitized with BSA emulsified with Freund's complete adjuvant (FCA) and given DL-propranolol as a shock potentiator, a similar pattern of drug susceptibility as that in the pertussis-vaccinated animals was obtained in general, although a discrepancy was seen with regard to the suppression of CV-6209 in C3H/HeN and BDF1 mice. Synergistic suppression by CV-6209 and cyproheptadine was also very clear with the WBB6F1-+/+ mice sensitized using FCA. In addition, results quite similar to those with cyproheptadine were obtained with the other two antihistamines, triprolidine almost devoid of antiserotonin activity and oxatomide, in testing with BDF1 mice sensitized using Bordetella pertussis organisms. From these findings, the conclusion is that histamine and PAF play major roles solely or in combination in mouse active anaphylactic shock.