Objective To evaluate gene polymorphisms and their association with susceptibility to dengue. Methods A retrospective case-control study was performed with 262 subjects, comprising 78 dengue fever (DF) patients, 49 dengue hemorrhagic fever (DHF) patients and 135 healthy controls. Genotypic and allelic profiles were identified using polymerase chain reaction based in real time and amplification-refractory mutation system. Results We observed a protective association of IL-10 (−819 C/T) C allele (P = 0.028, OR = 0.56, CI = 0.34–0.91) against DHF, while the C/T (P = 0.047, OR = 2.10, CI = 1.01–4.38) and T/T (P = 0.008, OR = 3.82, CI = 1.38–10.59) genotypes were associated with DHF and DF, respectively. The dominant model TNFA −308 GA + AA (P = 0.043, OR = 0.45, CI = 0.20–1.00) genotypes were found to have protective effect against dengue infection. A protective association among the IFNG (+874 A/T) A/T genotype against DF (P = 0.02, OR = 0.46, CI = 0.24–0.89) and DHF (P = 0.034, OR = 0.43, CI = 0.19–0.95) was observed. When the studied single-nucleotide polymorphism was analyzed in combination, the combination GTA (P = 0.022, OR = 2.95, CI = 1.18–7.41) was statistically significantly associated with susceptibility to DF and the combination GCT (P = 0.035, OR = 0.28, CI = 0.08–0.90) with protection against the development of DHF. Conclusions This research identifies the association of the IFNG (+874 A/T), TNFA (−308G/A), IL-10 (−819 C/T) genotypes as a factor for protection, susceptibility and severity to dengue.