Ovarian cancer is the single most deadly form of women’s cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of ovarian cancer and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, that disrupts a let-7 microRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from non-selected ovarian cancer patients in three independent cohorts, two independent ovarian case-control studies, and ovarian cancer patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as in their family members. Our results indicate that the KRAS-variant is associated with greater than 25% of non-selected ovarian cancer cases. Further, we found that it is a marker for a significant increased risk of developing ovarian cancer, as confirmed by two independent case control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing ovarian cancer, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities.