BackgroundHypomethylation of the aryl hydrocarbon receptor repressor (AHRR) gene indicates long-term smoking exposure and might therefore be a monitor for smoking-induced disease risk. However, studies of individual longitudinal changes inAHRRmethylation are sparse.Research QuestionHow does the recovery ofAHRRmethylation depend on change in smoking behaviors and demographic variables?Study Design and MethodsThis study included 4,432 individuals from the Copenhagen City Heart Study, with baseline and follow-up blood samples and smoking information collected approximately 10 years apart.AHRRmethylation at the cg05575921 site was measured in bisulfite-treated leukocyte DNA. Four smoking groups were defined: participants who never smoked (Never-Never), participants who formerly smoked (Former-Former), participants who quit during the study period (Current-Former), and individuals who smoked at both baseline and follow-up (Current-Current). Methylation recovery was defined as the increase inAHRRmethylation between baseline and follow-up examination.ResultsMethylation recovery was highest among participants who quit, with a median methylation recovery of 5.58% (interquartile range, 1.79; 9.15) vs 1.64% (interquartile range, –1.88; 4.96) in the Current-Current group (P< .0001). In individuals who quit smoking, older age was associated with lower methylation recovery (P< .0001). In participants who quit aged > 65 years, methylation recovery was 5.9% at 5.6 years after quitting; methylation recovery was 8.5% after 2.8 years for participants who quit aged < 55 years.InterpretationAHRRmethylation recovered after individuals quit smoking, and recovery was more pronounced and occurred faster in younger compared with older interim quitters.