Background: We conducted this study to identify the influences and synergistic effects of smoking status and polymorphisms in hedgehog interacting protein (HHIP) on chronic obstructive pulmonary disease (COPD) and lung function decline. Methods: A cohort containing 306 COPD patients and 743 healthy subjects was recruited from 25,000 subjects. All selected subjects had chronic cough for over 2 years or a smoking history above 20 pack-years. After 8 years, all subjects were divided into 2 cohorts according to whether they had quit smoking or not. A follow-up of all patients was completed after another period of 10 years. Three variants in HHIP were genotyped to investigate the impacts of gene susceptibility on the development of COPD and lung function decline. Results: During the follow-up tests, forced expiratory volume in 1 s (FEV1) ratios decreased more significantly in COPD patients than in healthy subjects. For variant rs7654947, FEV1 decreased more significantly in CC and CT subjects than in TT subjects. FEV1 in COPD patients with a CC genotype from smoking cohorts reduced markedly when compared to ex-smoking cohorts (case, 30.75% vs. 35.5%; total, 28% vs. 32%). Conclusions: Our results showed that smoking and HHIP variant rs7654947 were associated with COPD development and lung function decline. Moreover, we found that cigarette smoking and gene susceptibility have cooperative effects on COPD risk and lung function decline.