SummaryBackground Atrial natriuretic peptide (ANP) plays an important role in the lung and in augmenting allergic inflammation in asthma. The gene encoding ANP, NPPA, is located on chromosome 1p36, a region that has been linked to asthma.Objectives Determine associations between asthma and four common SNPs on the NPPA gene: C/G (rs13305986) in the promoter; G/A (rs5063) in Exon 1 resulting in NPPAMet32→Val substitution; T/C (rs5065) in Exon 3 resulting in an Arg152→Ter substitution; and T/C in the 3′UT region (rs5067).Methods A case–control design was used in White participants. The screening cohort consisted of 336 asthmatic cases who participated in a large clinical trial and 154, non‐asthmatic controls. The replicate cohort consisted of 172 asthmatic cases from a second clinical trial and 115 healthy controls. Demographic characteristics were well matched for cases and controls in the screening cohort. Adjusted (age, gender, body mass index) odds ratio (OR) were calculated by χ2 and logistic regression; a P‐value of 0.0167 defined the threshold of significance.Results The C allele of rs5067 was associated with asthma in the screening and replicate cohorts: adjusted ORs (95% confidence intervals) 0.5 (0.29–0.84; P=0.009) and 0.24 (0.11–0.53; P<0.0001), respectively. The C allele of rs5065 was associated with asthma in the screening cohort but not in the replicate. The population‐attributable risk for asthma in carriers of the C allele for rs5067 was 23.3%.Conclusions For rs5067, the risks of asthma in carriers of the C allele in the screening and replicate cohorts were reduced by 50% and 76%, respectively. NPPA may be an important susceptibility gene for asthma.