Red cells exposed to glycophorin A reactive antibodies and lectins develop a non-specific cation permeability. To determine if this might be due to the activation of a non-selective mechanosensitive channel we have subjected red cells, loaded with a calcium responsive fluorescent probe, to filtration through 5 and 3 microm pores. Calcium entered 28% of normal red cells at the moment of deformation when 3 microm filtered, a finding consistent with the transient activation of a mechanosensitive channel. Red cells containing hemoglobin AC and AS had enhanced calcium responses to filtration. An increased influx of calcium in hemoglobin disorders might play a role in providing protection against Falciparum malaria.