Aim: Previous studies suggest telomere shortening represses PGC1A and PGC1B expression leading to mitochondrial dysfunction. Methylation of CpG sites within these genes may interact with these factors to affect cancer risk. Materials & methods: Among 385 men, we identified 84 incidents of cancers (predominantly prostate and nonmelanoma skin). We examined associations between leukocyte DNA methylation of 41 CpGs from PGC1A and PGC1B with telomere length, mitochondrial 8-OHdG lesions, mitochondrial abundance and cancer incidence. Results: Methylation of five and eight CpG sites were significantly associated with telomere length and mitochondrial abundance at p < 0.05. Two CpG sites were independently associated with cancer risk: cg27514608 (PGC1A, TSS1500; HR: 1.55, 95% CI: 1.19–2.03, FDR = 0.02), and cg15219393 (PGC1B, first exon/5′UTR; HR: 3.71, 95% CI: 1.82–7.58, FDR < 0.01). Associations with cg15219393 were observed primarily among men with shorter leukocyte telomeres. Conclusion: PGC1A and PGC1B methylation may serve as early biomarkers of cancer risk.