Epidemiologic studies have linked shortened telomeres with the development of many cancers. However, recent studies have suggested that longer telomeres may lead to prolonged senescence in melanocytes, providing increased opportunity for malignant transformation. We therefore examined whether shorter prediagnostically measured relative telomere length in peripheral blood leukocytes (PBL) was associated with a decreased risk of cutaneous melanoma. Telomere length in prospectively collected PBLs was measured in incident melanoma cases and age-matched controls selected from participants in three large prospective cohorts: the Women's Health Initiative Observational Study (WHI-OS), the Health Professionals Follow-up Study (HPFS), and the Nurses' Health Study (NHS). Shorter telomere lengths were associated with decreased risk of melanoma in each cohort. The P(trend) across quartiles was 0.03 in the WHI-OS and 0.008 in the HPFS. When combining these two datasets with published data in the NHS (P(trend), 0.09), compared with individuals in the fourth quartile (the longest telomere lengths), those in the first quartile had an OR of 0.43 (95% CI: 0.28-0.68; P(trend), 0.0003). Unlike findings for other tumors, shorter telomeres were significantly associated with a decreased risk of melanoma in this study, suggesting a unique role of telomeres in melanoma development.