Abstract Ovarian cancer remains the most lethal gynecological malignancy due to the lack of highly sensitive and specific screening tools for detection of early-stage disease. The goal of the proposed study is to explore the viability of a novel Piwi-interacting RNA (piRNA)-based detection tool for the early detection of ovarian cancer. PiRNAs are an abundant class of small (26-32 nt) noncoding RNAs with over 30,000 known human members and play a pivotal role in the maintenance of genomic stability via epigenetic silencing of transposable elements (TE). Recent evidence from our group and others has suggested that piRNAs can also induce DNA methylation at non-TE protein coding genes, including cancer-related genes in somatic cells. Our ongoing analyses have observed marked differences in expression of several piRNAs between ovarian cancer tissues and normal ovarian tissues. As a novel group of small noncoding RNAs, no published work has examined the potential use of piRNAs for the early detection of ovarian cancer. The proposed study will test the hypothesis that piRNAs can serve as a novel group of blood-based biomarkers for the early detection of ovarian cancer. We will perform piRNA sequencing (piSeq) analysis to detect over-expressed piRNA candidates in 1) early stage (I-II) ovarian tumor tissues compared to fallopian tube tissues from control subjects (Aim 1) and 2) in serum samples from early stage (I-II) ovarian cancer patients compared to matched normal subjects (Aim 2). This exploratory study will provide proof of concept for future large population-based studies to further investigate the translational role of piRNA in ovarian cancer, which would accelerate our understanding of the role of piRNAs in ovarian tumorigenesis and provide new avenues of research to facilitate the development of innovative diagnostic biomarkers for ovarian cancer.