Contributions of environmental and genetic factors to IgG subclass responses against Plasmodium falciparum antigens RESA and MSP2 were investigated among adults in a highly endemic area of Papua New Guinea. Heritabilities were estimated using variance component analysis. Familial aggregation of several responses was found, including IgG1, IgG2 and IgG3 responses against RESA, IgG1 and IgG3 responses against the 3D7 form of MSP2 and IgG1, IgG2 responses against the FC27 form of MSP2. Allowance for sharing of houses explained some of the non-genetic variance but not the familial aggregation. The variance of IgG3 responses against RESA and IgG1, IgG2 against MSP2 (FC27) was partly explained by sharing of HLA class II genotypes, although heritability was low. Segregation analyses indicated that any genetic regulation was more complex than governed by a single major gene. Such host genetic variation in responses to specific malaria antigens has implications for immuno-epidemiology and vaccine development.