Plasmodium falciparum merozoite surface antigen 2 (MSA2) is considered a vaccine candidate in a subunit vaccine against blood stage malaria. In order to test if a specific genotype of the highly polymorphic MSA2 is associated with disease, we conducted a case-control study in a malaria endemic area of Papua New Guinea involving 227 individuals, mostly children under the age of 10 years. All cases and controls were genotyped by polymerase chain reaction for their respective MSA2 genotypes. We report that at the time of the study parasites carrying the FC27-like genotype were twice as likely to be found in symptomatic malaria cases than in asymptomatic controls. Mixed genotype infections were significantly less frequent in symptomatic malaria infections. One individual allele (WOS10) of the FC27 family was found only in cases. This may be a form of P. falciparum infrequently encountered and may cause morbidity due to lack of immunity to it. This study provides evidence that MSA2 is involved in the morbidity of malaria and supports the inclusion of MSA2 in a subunit vaccine.