Cerebral malaria (CM) is the most severe complication caused by Plasmodium falciparum infection. The pathophysiological changes caused by parasite virulence factors and the human immune response to parasites contribute to CM. To date, very few parasite virulence proteins have been found to participate in CM. Here, we employed comparative genomics analysis and identified parasite-infected erythrocyte specific protein 2 (PIESP2) to be a CM-related protein. We conducted further experimental investigations and found that PIESP2 is an immunogenic protein.