Kisspeptin is a 54 amino acid peptide, encoded by the anti-metastasis gene KiSS-1, that activates the G-protein-coupled receptor, GPR54. The kisspeptin/GPR54 system is critical to normal reproductive development. KiSS-1 gene expression is increased in the human placenta in normal and molar pregnancies. Circulating kisspeptin is dramatically increased in normal pregnancy but levels in gestational trophoblastic neoplasia (GTN) have not previously been reported. The present study was designed to determine if plasma kisspeptin levels are altered in patients with malignant GTN. Thirty nine blood samples were taken from 11 patients with malignant GTN at presentation, during and following chemotherapy. Blood was also sampled from non-pregnant and pregnant volunteers. Plasma kisspeptin immunoreactivity (-IR) and human chorionic gonadotrophin (hCG) concentrations were measured. Plasma kisspeptin-IR concentration in non-pregnant (n=16) females <2 pmol/L. Plasma kisspeptin-IR in females in the first trimester of pregnancy (n=13) was 803 ± 125 pmol/L, in the third trimester of pregnancy (n=7) was 2483 ± 302 pmol/L and day 15 post partum (n=7) was <2 pmol/L. Plasma kisspeptin-IR and hCG concentrations in patients with malignant GTN were elevated at presentation and fell during and following treatment with chemotherapy in each patient (mean plasma kisspeptin-IR: pre-chemotherapy 1363 ± 1076 pmol/L vs. post-chemotherapy <2 pmol/L, p<0.0001. Mean plasma hCG: pre-chemotherapy 227191 ± 152354 U/L vs. post-chemotherapy 2 U/L, p<0.0001). Plasma kisspeptin-IR strongly positively correlated with plasma hCG levels (r²=0.99, p<0.0001). Our results suggest that measurement of plasma kisspeptin-IR may be a novel tumor marker in patients with malignant GTN.