Previous works have demonstrated the involvement of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and nuclear factor kappa B (NF-κB) in maintaining the normal physiology of the heart. Polymorphisms in genes encoding these proteins may affect their normal functions, which could subsequently lead to chronic heart failure (CHF). In this work, we examined the association of CTLA4 and NFKB1 polymorphisms with CHF in a Chinese population. The −318C>T and +49A>G polymorphisms of CTLA4 and −94 insertion/deletion ATTG polymorphism of NFKB1 were genotyped on 538 patients with CHF and 1076 healthy controls. Our data indicate that the CTLA4 +49A>G and NFKB1 polymorphisms could confer susceptibility to CHF among Chinese. A significantly increased CHF risk was observed for the mutant CTLA4 +49GG genotype ( P = 0.0093), and both heterozygous ATTG1/ATTG2 ( P = 0.0142) and mutant ATTG2/ATTG2 ( P = 0.0018) genotypes of NFKB1 . Our data suggest that there is a potential use of these polymorphisms for early genetic screening for CHF.