Peptidyl arginine deiminases (PADs) are a family of calcium-binding enzymes that catalyze the citrullination of arginine and methylarginine residues as a form of gene regulation. The overexpression of PADs has been found to correlate with negative health outcomes in both autoimmune diseases and cancer. Particularly, the overexpression of PAD4 in cancer cells contributes to tumorigenesis and metastasis through the accelerated formation of histone citrullination-mediated neutrophil extracellular traps (NETs) and the downregulation of the p53 pathway. Significantly elevated PAD4 levels have been observed in various ovarian cancer subtypes, and it has been proposed that this elevation is a significant contributor to the malignancy of these cancers. Thus, the purpose of this experiment was to explore the effect of Cl-amidine, a small organic compound and irreversible inhibitor of PAD4, on human ovarian adenocarcinoma cells. In addition, Cl-amidine has been indicated to have potentially synergistic interactions with rapamycin, an established anticancer drug, against breast cancer cells. Therefore, the potential for Cl-amidine and rapamycin to act synergistically against ovarian adenocarcinoma was also explored. MTT cell viability, LDH cytotoxicity, and caspase activation assays were used to determine the effect of Cl-amidine alone or in conjunction with rapamycin on ovarian cancer cells. Cl-amidine alone ultimately resulted in 70% cancer cell death, while Cl-amidine in combination with rapamycin resulted in nearly 90% cancer cell death. Both compounds were shown to have negligible effects on noncancerous cell lines. Modified synergy checkerboard assays showed consistent synergistic activity (FIC₅₀<0.5) between Cl-amidine and rapamycin. RT-PCR assays were used to demonstrate that Cl-amidine also altered the expression of PAD4 and p53-associated genes. Therefore, Cl-amidine alone or in conjunction with rapamycin may be a new treatment option for ovarian cancer.