Adult lung resident stem/progenitor cells, including P63 progenitor cells, have demonstrated the capacity for regeneration of lung epithelium in preclinical models. Here, we report a clinical trial of intrapulmonary P63 progenitor cell transplantation in 28 participants with stage II to IV chronic obstructive pulmonary disease (COPD). Autologous P63 progenitor cells were isolated from the airway basal layer of participants in the intervention group via bronchoscopic brushing, cultured for 3 to 5 weeks, and then transplanted back into the lungs via bronchoscopy at 0.7 × 10 to 5.2 × 10 cells per kilogram of body weight. Twenty patients were evaluable at the end of the study (intervention group, = 17; control group, = 3). No grade 3 to 5 adverse events (AEs) or serious AEs occurred. Although bronchoscopy-associated AEs were recorded in participants in the intervention group, other AEs were not substantial different between groups. Twenty-four weeks after transplantation, participants in the intervention group displayed improvement in gas transfer capacity [diffusing capacity of the lung for carbon monoxide (DLCO) change from baseline: +18.2%], whereas the control group experienced a decrease (DLCO change from baseline: -17.4%; = 0.008). Furthermore, participants in the intervention group showed >30-meter increase in walking distance within 6 minutes. Transcriptomic analysis of progenitor cells isolated from responding and nonresponding individuals in the intervention group showed that higher expression of was associated with treatment efficacy. In conclusion, transplantation of cultured P63 lung progenitor cells was safe and might represent a potential therapeutic strategy for COPD.