Pregnancy loss and neonatal mortality have a significant economic impact on the equine industry. Placentitis is a common cause of abortion, stillbirths, and neonatal infections. Early diagnosis of placentitis allows prompt treatment and increases the chances of a pregnancy reaching term. Our study was designed to identify blood parameters that are diagnostic of imminent placentitis under natural conditions. We hypothesized that differences from physiological parameters of a healthy pregnancy indicate imminent placentitis. Blood sample collections and reproductive exams were prospectively performed, monthly, between 180 to 320 days of gestation, in a cohort of mares from 2 large broodmare herds in Lexington, KY. Twelve mares were diagnosed with placentitis based on rectal ultrasonographic examination (opening at the cervix, thickened placenta, fluid collection, placental edema, and/or placental separation). Blood samples collected on the day of placentitis diagnosis were designated as early onset, and the blood samples collected in the previous reproductive exam with no ultrasonographic abnormalities of the fetoplacental unit were named as pre-onset (before placentitis diagnosis). In addition, 12 gestion and age-matched control mares carrying healthy pregnancies based on the same parameters were paired to the mares with placentitis. We measured several immunological, inflammatory, and hormonal parameters (Table 1). Values were compared between groups within the same timepoint (placentitis vs control) and between timepoints (pre-onset vs early onset) using Paired Student's T test and Mann-Whitney U test, and significance set at p < 0.05. According to the gestational age, the interval between pre-onset timepoint and the diagnosis of placentitis (early onset) was around 40 days (227±6 days and 267±5 days, respectively).No differences were found between groups and timepoints for immunological and inflammatory parameters in the maternal circulation, including serum amyloid A (SAA) and alpha-fetoprotein (AFP). Both proteins have been shown to markedly increase in maternal circulation after experimental induction of placentitis. In the hormonal analyses, no differences were found in plasma progesterone levels and estradiol-17β/progesterone ratio. Plasma estradiol-17β concentration approached statistical difference (p=0.08) in mares at early onset of placentitis (408±35 pg/mL) compared to the control group (498±35 pg/mL). In conclusion, our data showed that early events of spontaneous placentitis do not increase inflammatory and immunological parameters in the maternal circulation. In addition, plasma estradiol-17β may be further investigated as an early indicator of placental dysfunction in mares with naturally occurring placentitis. Acknowledgments: We thank the Harry M. Zweig Memorial Fund for Equine Research for supporting our study.