Background: Chronic inflammation plays a key role in cancer etiology. DNA methylation modification, one of the epigenetic mechanisms regulating gene expression, is considered a hallmark of cancer. Human and animal models have identified numerous links between DNA methylation and inflammatory biomarkers. Our objective was to prospectively and longitudinally examine associations between methylation of four inflammatory genes and cancer risk. Methods: We included 795 Normative Aging Study participants with blood drawn one to four times from 1999 to 2012 (median follow-up, 10.6 years). Promoter DNA methylation of IL6, ICAM-1, IFN, and TLR2 in blood leukocytes was measured using pyrosequencing at multiple CpG sites and averaged by gene for data analysis. We used Cox regression models to examine prospective associations of baseline and time-dependent methylation with cancer risk and compared mean methylation differences over time between cancer cases and cancer free participants. Results: Baseline IFN hypermethylation was associated with all-cancer (HR, 1.49; P=0.04) and prostate cancer incidence (HR, 1.69; P = 0.02). Baseline ICAM-1 and IL6 hypermethylation were associated with prostate cancer incidence (HR, 1.43; P=0.02; HR, 0.70; P=0.03, respectively). In our time-dependent analyses, IFN hypermethylation was associated with all-cancer (HR, 1.79; P = 0.007) and prostate cancer (HR, 1.57; P = 0.03) incidence; and ICAM-1 and IL6 hypermethylation were associated with prostate cancer incidence (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, respectively). We detected significant ICAM-1 hypermethylation in cancer cases (P = 0.0003) 10 to 13 years prediagnosis. Conclusion: Hypermethylation of IFN and ICAM-1 may play important roles in early carcinogenesis, particularly that of prostate cancer. Impact: These methylation changes could inform the development of early detection biomarkers and potential treatments of inflammation-related carcinogenesis.