Toevaluate theroleoferythrocyte (RBC) membrane proteins intheinvasion andmaturation ofPlasmo- diumfalckqarum, wehavestudied, inculture, abnormal RBCs containing quantitative orqualitative membrane protein de- fects. These defects included hereditary spherocytosis (HS)due todecreases inthecontent ofspectrin (HS(Sp+)), hereditary elliptocytosis (HE)duetoprotein 4.1deficiency (HE(4.10)), HE duetoaspectrin aIdomain structural variant that results in increased content ofspectrin dimers (HE(Spav"')), andband 3structural variants. Parasite invasion, measured bytheinitial uptake of(3H1hypoxanthine 18hrafter inoculation withmero- zoites, wasnormal inallofthepathologic RBCs.Incontrast, RBCsfromsixHS(Sp+) subjects showedmarkedgrowth inhibition that became apparent after thefirst orsecond growth cycle. Preincubation ofHS(Sp+) RBCsinculture for3daysdid notalter these results. Normal parasite growth wasobserved in RBCsfromoneHSsubject withnormal membrane spectrin content. Theextent ofdecreased parasite growth inHS(Sp+) RBCsclosely correlated withtheextent ofRBC spectrin deficiency (r= 0.90). Homogeneous subpopulations ofdense HS RBCsexhibited decreased parasite growth tothesame extent asdidHSwholeblood. RBCsfromfourHE subjects showed markedparasite growth inhibition, theextent ofwhich correlated withthecontent ofspectrin dimers (r=0.94). RBCs fromtwounrelated subjects withstructural variants ofband3 sustained normalparasite growth. Decreased growth inthe pathologic RBCswasnottheresult ofdecreased ATPor glutathione levels orofincreased RBChemolysis. Weconclude thatabnormal parasite growthinthese RBCsisnotthe consequence ofmetabolic orsecondary defects. Instead, we suggest that afunctionally andstructurally normal host mem- braneisindispensable forparasite growth anddevelopment. Several erythrocyte (RBC) genetic defects, particularly those withpolymorphic genefrequencies, havemostlikely been expanded inhumanpopulations bytheselective pressure of Plasmodium falciparum malaria (1). Amongthese areaand ,Bthalassemias, ovalocytosis, glucose-6-phosphate dehydro- genase deficiency, andhemoglobinopathies produced bythe presence ofhemoglobin (Hb)S,HbC,andHbE.Advances havebeenmadeinourunderstanding bywhichthese RBC genetic defects partially protect thebearer fromtheeffects of themalaria infection. Hereditary spherocytosis (HS) andhereditary elliptocytosis (HE)belong toadifferent category because these genetic defects havenotbeenreported atpolymorphic frequencies in anyregion oftheworld. Nevertheless, since theunderlying molecular defect ofthese RBCsis, inmanycases, adefinable cytoskeletal protein abnormality, itisofgreat interest to investigate thefate ofP.falciparum malaria parasites inthese RBCsandtoexplore thepossibility thathostmembrane proteins arenecessary forintraerythrocyti c parasite develop- mentbeyond theinitial encounter during invasion. Inthis paperwe examine themalarial growth patterns inthese abnormal RBCs.We haveutilized unrelated families with spectrin-deficient HSRBCs(HS(Sp'); nomenclature ofskel- etal proteins asproposed inref. 2),although exhibiting differ- entdegrees ofspectrin deficiency; HE RBCswitheither complete deficiency ofprotein 4.1(HE(4.10)) orcontaining a spectrin aIdomain structural variant (HE(Spa'65)); andRBCs containing band3structural variants.