Background: In a cross-sectional study, we previously showed that cystic fibrosis phenylalanine-508 deletion (ΔF508) heterozygosity may be overrepresented among individuals with asthma. Objective: Using 15-year follow-up data from the Copenhagen City Heart Study, we now further explore this relationship. Methods: As part of 3 surveys in 1976 to 1978, 1981 to 1983, and 1991 to 1994, we measured pulmonary function and asked all participants about asthma and pulmonary risk factors. Results: There was no difference in annual decline in lung function between ΔF508 heterozygotes and noncarriers overall; however, among individuals with familial asthma, the annual declines in FEV1 and forced vital capacity (FVC) were 49 and 36 mL in ΔF508 heterozygotes versus 24 and 17 mL in noncarriers (P = .01 and P = .12, respectively). Cross-sectionally based on triple measurements, FEV1 and FVC in individuals aged 20 to 70 years were lower in heterozygous participants versus noncarriers (P = .02 and P = .004, respectively). The average reduction of FEV1 and FVC in ΔF508 heterozygotes versus noncarriers was 70 mL (P = .06) and 136 mL (P = .008). Finally, 10% of carriers reported asthma versus 7% of noncarriers (P = .02), resulting in an odds ratio of 2.0 (1.3-3.2) for asthma in ΔF508 heterozygotes. Conclusion: Cystic fibrosis ΔF508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than noncarriers. Furthermore, ΔF508 heterozygosity in context with familial predisposition to asthma may be associated with a greater annual FEV1 decline.