Purpose: CWP is an untreatable but preventable fibrotic lung disease caused by the chronic inhalation of coal dust. Genetic factors such as polymorphisms play an important role in the development of CWP. The present study investigated the association between the polymorphisms of SMAD4 and NLRP3 and CWP risk in a Chinese Han population. Patients and Methods: SMAD4 rs10502913 and NLRP3rs1539019 polymorphisms were examined in 292 CWP subjects and 315 coal dust-exposed controls. The genotypes were analyzed using direct sequencing. The allele and genotype proportion between the cases and controls were compared using the chi-square test. Results: The AG and GG genotypes of SMAD4 rs10502913 were not associated with altered CWP risk compared with AA genotype (adjusted OR = 1.535 and 1.426, 95% CI = 0.785-3.000 and 0.732-2.781, p = 0.210 and 0.297, respectively). Also, the NLRP3 rs1539019 heterozygous and homozygous variants CA and CC genotypes were not associated with the risk of CWP compared with the AA genotype (adjusted OR = 0.985 and 1.127, 95% CI = 0.652-1.489 and 0.713-1.782, p = 0.944 and 0.608, respectively). In addition, there was no interaction between SMAD4 rs10502913 and NLRP3 rs1539019 genotypes and smoking status on CWP risk in the stratified analyses. Conclusion: In this present study, SMAD4 rs10502913 and NLRP3 rs1539019 genotypes were not associated with altered CWP risk in the Chinese Han population. Large sample sizes and multicenter studies are needed to elucidate these results in the future.