Abstract Purpose: Increasing chronological age is a risk factor for many types of cancer including colorectal. An understanding of the biology of aging and factors which regulate it may provide insight into cancer pathogenesis. The role of telomere biology in both the cancer and aging process could prove useful in this regard. Experimental Design: Using quantitative PCR, we determined telomere length in the peripheral blood leukocytes of 64 colorectal cancer (CRC) patients and 1,348 controls. We also measured telomere length in 32 colorectal tumor samples and matched normal tissue. We aimed to assess whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A, a circulating modulator of calcium homeostasis. Results: CRC patients had shorter telomeres [adjusted mean ratio of relative telomere repeat copy number to single-copy gene number (RelT/S) = 0.61] compared with chronologically older controls (mean age = 75, adjusted mean RelT/S = 0.70; ANCOVA, P = 0.004). Telomere length in tumor tissue [median = 0.43, interquartile range (IQR) = 0.40] was significantly shorter than adjacent normal tissue (median = 0.65, IQR = 0.28; P = 0.004). Patients with low fetuin-A levels were shown to have significantly shorter telomeres (P = 0.041). Patients with rectal tumors had significantly higher levels of fetuin-A than those with colonic tumors (P = 0.045). Conclusions: We have observed that patients with CRC display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological aging in the pathogenesis of CRC. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in our patients. Furthermore, fetuin-A levels can be used to distinguish between colon and rectal cancers. Clin Cancer Res; 17(17); 5573–81. ©2011 AACR.