To analyze and study the correlation between NLR family CARD domain-containing 4 (NLRC4) gene single nucleotide polymorphisms and the prognosis of patients with hemophagocytic lymphohistiocytosis (HLH).In this study, we retrospectively studied the clinical data of 62 HLH patients, including 40 males and 22 females. The genomic DNA was extracted, and the genotypes at rs385076 locus and rs479333 locus of the NLRC4 gene were analyzed. The level of blood interleukin-18 (IL-18) was analyzed by enzyme-linked immunosorbent assay (ELISA).Compared with the TT genotype at the NLRC4 gene rs385076 locus, the mortality of HLH patients with TC genotype and CC genotype was higher (RR = 3.205, 95% CI: 1.277-4.788, p = 0.012; RR = 3.052, 95% CI: 1.098-4.753, p = 0.031). Taking the CC genotype at rs479333 of the NLRC4 gene as a reference, HLH patients with CG genotype and GG genotype had a higher risk of death (RR = 3.475, 95% CI: 1.488-5.775, p = 0.003; RR = 2.986, 95% CI: 1.014-5.570, p = 0.047). NLRC4 gene rs385076 T>C and rs479333 C>G were significantly related to the poor prognosis of HLH patients. The area under the curve (AUC) of the receiver operating curve (ROC) for the prognostic outcome of HLH with serum IL-18 level was 0.6813 (95% CI: 0.5365-0.8260, p = 0.0189). NLRC4 gene rs385076 T>C and rs479333 C>G were related to higher serum IL-18 levels.NLRC4 gene rs385076 T>C and rs479333 C>G are related to the poor prognosis of HLH patients.Copyright © 2021 Yan Li et al.