Telomerase is reactivated in over 90% of tumors and plays critical roles in tumor progression. The mechanisms by which telomerase is up-regulated in cancer cells are poorly understood. Here we showed that a bioactive lipid, lysophophatidic acid (LPA), up-regulated the expression of human telomerase reverse transcriptase (hTERT) and telomerase activity in serous ovarian adenocarcinoma cell lines SKOV3, A2780, and HEY, but not in OCC1, a clear cell ovarian cancer cell line. This cell type specific effect of LPA on telomerase regulation may reflect distinctive genetic backgrounds in different histological subtype of ovarian cancer cells. Our data further suggest that the phosphatidylinositol 3-phosphate kinase (PI3K) pathway and hypoxia-inducible factor-1alpha (HIF-1alpha) are likely to be involved in LPA-induced hTERT expression. Targeting human telomerase by LPA is potentially involved in its role of promoting tumor progression.