Prokineticin 1 (PROK1) is a recently described protein with wide range of functions including tissue specific angiogenesis, modulation of inflammatory responses and regulation of hematopoiesis. The objective of this study was to investigate the role of PROK1 and prokineticin receptor 1 (PROKR1) in human endometrium during early pregnancy. PROK1 and PROKR1 expression is significantly elevated in first trimester decidua compared with non-pregnant endometrium. Expression of PROK1 and PROKR1 was localised in glandular epithelial and various cellular compartments within the stroma. In order to investigate the signalling pathways and target genes activated by PROK1, we generated an endometrial epithelial cell line stably expressing PROKR1 (Ishikawa PROKR1 cells). PROK1-PROKR1 interaction induced inositol phosphate mobilisation and sequential phosphorylation of cSrc, EGFR and ERK 1/2. Gene microarray analysis on RNA extracted from Ishikawa PROKR1 cells treated with 40nM PROK1 for 8 hours revealed 49 genes to be differentially regulated. A number of these genes, including COX-2, LIF, IL-6, IL-8 and IL-11 are regulated in the endometrium during implantation and early pregnancy. We subsequently investigated the effect of PROK1 on expression of COX-2 in Ishikawa PROKR1 cells and first trimester decidua. COX-2 mRNA and protein expression, and prostaglandin synthesis, were elevated in response to treatment with PROK1. Moreover, expression of COX-2 by PROK1 was dependent on activation of the Gq-PLC-cSrc-EGFR-MEK pathway. These data demonstrate that PROK1 and PROKR1 expression is elevated in human decidua during early pregnancy and that PROK1-PROKR1 interaction regulates expression of a host of implantation related genes.