The antibody response against the malaria vaccine SPf66 and against circumsporozoite (CS) protein has been tested in immune adults from a malaria endemic area in Papua New Guinea. All individuals were genotyped for the HLA class II DQB1 and DRB1 loci, and the humoral response was analyzed with respect to the identified class II alleles. At each locus, only three alleles were frequent, namely DRB1*11, *15, and *16, and DQB1*0301, *0502, and *0601. Antibodies against SPf66 and CS protein were found in 84% and 79% of the individuals, respectively. A strong negative association was detected between the humoral response against SPf66 and DRB1*15 and DQB1*0601. A positive association of the response was observed with DRB1*11 and DQB1*0301. After analysis with a multiple regression model in which all alleles were included simultaneously, only DRB1*15 remained significantly associated with low antibody responses. This suggests that nonresponders may be expected after immunization with SPf66 in certain populations.