ARTICLE ABSTRACTBackground: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047).Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases.Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.