Thrombocytopenia is a common occurrence in moderate to severe crotaline envenomation. The exact mechanism by which rattlesnake venom leads to thrombocytopenia is unclear, but aggressive treatment with crotaline-specific antivenom often leads to resolution of this disorder. Crotalinae Polyvalent Immune Fab (CroFab(TM), Protherics Inc., Nashville, TN) (crotaline Fab) is now available for the treatment of symptomatic rattlesnake envenomation. Although recurrence of thrombocytopenia has been reported in patients after envenomation treated with crotaline Fab, cases refractory to this therapy have not been described. We report a case of severe crotaline envenomation that appears to have exhibited two separate episodes of thrombocytopenia, only one of which responded to antivenom. The second, later phase was refractory to both crotaline Fab as well as traditional Antivenin (Crotalinae) Polyvalent (Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA) (ACP). By reviewing the literature regarding venom-induced thrombocytopenia, we attempt to explain this "biphasic" phenomenon and the inability of crotaline Fab to reverse this toxic effect.