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Simple Summary: Since the discovery of a BRCA1 mutation nearly 30 years ago, definitive methods for ovarian cancer-risk reduction has remained unchanged, requiring carriers of a pathogenic mutation to consider undergoing surgical removal of both fallopian tubes and ovaries from the ages of 35 to 40 years. The sequelae of these invasive measures include a profound impact on general health, psychological well-being, sexual and reproductive function. Identifying targetable aberrances in BRCA1 mutation carriers, such as sex hormones, or adopting mechanisms aimed at enhancing tumor immunosurveillance may facilitate the reduction of early cancer-promoting events. This is particularly relevant for the fimbrial fallopian tube, where the majority of epithelial ovarian cancers originate. Utilizing a proof-of-concept for potentially targetable aberrances may further the development of non-surgical adjuncts or surveillance methods aimed at cancer-risk reduction for women deferring or declining surgery. Background: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3− CD56+ natural killer (NK) cells. Methods: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5β-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. Results: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. Conclusions: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition. [ABSTRACT FROM AUTHOR]