Host genetics in dengue hemorrhagic fever (DHF) pathophysiology has not been extensively investigated. Most studies have focused on HLA in different populations; however these reported associations have not been replicated. We performed a case-control study to analyze possible associations of HLA-A, HLA-B, HLA-Cw, HLA-DRB1 and HLA-DQB1 alleles with clinical disease severity caused by dengue virus infection. Our population consisted of 39 individuals (DF: 23, DHF: 16) and 34 healthy controls from the State of Morelos, Mexico. HLA loci were genotyped by nucleotide sequencing method. Statistical analyses revealed associations in three alleles: HLA-B*35 was negatively associated with symptomatic disease (p<1x10(-4), p(c)=0.01, OR=0.12, 95%CI=0.037-0.39), and DF (p=0.0007, p(c)=0.03, OR=0.13, 95%CI=0.031-0.51). HLA-DQB1*0302 was positively associated with DHF (p=0.018, p(c)=NS, OR=5.02, 95%CI=1.05-25.34), and negatively with DF (p=0.011, p(c)=NS, OR=0.23, 95%CI=0.06-0.84). HLA-DQB1*0202 was positively associated with DF only (p=0.012, p(c)=NS, OR=7.0, 95%CI=1.11-73.8). We identified possible associations of HLA-B and HLA-DQB1 alleles with the risk of developing symptomatic disease, DF and DHF in a Mexican Mestizo population.