The high degree of polymorphism of human leukocyte antigen (HLA) genes has been suggested to result from natural selection against susceptibility to a variety of infectious pathogens, including malaria. HLA molecules are considered to play a crucial role in the defense of the host against malarial infection, and different HLA class I and class II alleles have been reported to be associated with reduced susceptibility to malaria or the severity of malaria in different populations. To test for associations between HLA alleles and the severity of malaria in a Thai population, polymorphisms of HLA-B and HLA-DRB1 genes were investigated in 472 adult patients in northwest Thailand with Plasmodium falciparum malaria. In this study, malaria patients were classified into three groups: mild malaria, non-cerebral severe malaria, and cerebral malaria. Our results revealed that the allele frequencies of HLA-B46, -B56, and -DRB1*1001 were statistically different between non-cerebral severe malaria and cerebral malaria (P = 0.005), between mild malaria and cerebral malaria (P = 0.032), and between mild malaria and non-cerebral malaria (P = 0.007). However, our results may be showing false positives due to multiple testing. Thus, further study with a larger sample size must be conducted to obtain conclusive evidence of the association of these HLA-B and DRB1 alleles with the severity of malaria in Thailand.