In the Mouse Antithrombotic Assay aspirin (30-300 mg/kg) protected mice from death by 15 and 42%, respectively. Four Ca++ channel blockers (nitrendipine, nicardipine, nifedipine and verapamil) were effective in reducing the mortality. At the dose of 100 mg/kg nitrendipine and nicardipine gave 80 and 85% protection respectively. Whereas aspirin almost suppressed completely thromboxane (Tx)B2 and platelet factor-4 release after collagen-epinephrine infusion, neither nitrendipine nor nicardipine modified TxB2 release and only reduced slightly platelet factor-4 release. The treatment with aspirin, nitrendipine or nicardipine did not counteract the fall in circulating platelets counted 1 min after the aggregation challenge, but at 3 min platelet count was significantly higher in aspirin-treated mice than in animals given either Ca++ channel blocker. Mouse platelet aggregation induced in vitro by the combination of collagen and epinephrine was inhibited in samples obtained from mice pretreated with aspirin but was unaffected by the treatment with nitrendipine or nicardipine. The i.v. injection of a 12.5% suspension of hardened red blood cells resulted in death of about 80% of mice within 1 to 2 min. Neither circulating platelet count nor plasma TxB2 level were modified significantly by red cell injection. Aspirin was ineffective whereas both Ca++ channel blockers lowered mortality to 50%. These data suggest that Ca++ channel blockers reduce the mortality in the Mouse Antithrombotic Assay by influencing factors other than platelet aggregation and/or Tx production. These factors might be important in mediating mortality occurring after infusion of hardened red cells.