Operant conditioning of a spinal monosynaptic pathway using the Hoffman Reflex (H-reflex) is well established in animal and human studies. There is a subset within the human population (~ 20% non-responders) who are unable to up train this pathway suggesting some distinct or unique identifying characteristics. Importantly, females, who have a 9 times higher rate of injury during human performance activities than men, have been under-studied in areas of CNS neuroplasticity. Our long-term goal is to understand if innate ability to rapidly up train the H-reflex is predictive of future performance based injury among females. In this study, we determined whether healthy, young females could rapidly increase the H-reflex within a single session of operant conditioning and determined if electro-physiological, humoral, cognitive, anthropometric, or anxiety biomarkers distinguish the responders from non-responders. Eighteen females (Mean Age: 24) participated in the study. Ten females met the criteria for up training the H-reflex (responders). The responders showed lower levels of estradiol (P < 0.05) and trends for higher working memory (P = 0.06), higher maximal H-max/M-max ratio (P = 0.07), and higher basal metabolic rate (P = 0.07). A multivariate stepwise regression model supported that extracellular to intracellular water ratio (ECW/ICW) and H-max/M-max ratio explained 60% of the variation in the operant conditioning. These findings support that electro-physiological, hormonal, cognitive, and anthropometric characteristics are distinct among females capable of rapidly upregulating the H-reflex.