BACKGROUND: The CREST syndrome is an indolent form of progressive systemic sclerosis. Although its clinical progress is indolent, pulmonary hypertension(PH) associated with CREST syndrome have grave prognosis with over 40 percent mortality rate at 2 year follow-up. But the pathogenesis of pulmonary hypertension in this disease is not known, and classified as either primary or secondary PH. Clonality of endothelial cell proliferation in plexiform lesion is a molecular marker which allows distinction between primary and secondary PH. We performed this study to know whether the PH associated with CREST syndrome is a variant of primary PH or is a secondary PH. METHODS: We assessed the X-chromosome inactivation based on the methylation pattern of the human androgen-receptor gene by PCR(HUMARA). Endothelial cells in plexiform lesions from female patients(n=3) with PH associated with CREST syndrome were microdissected from paraffin blocks. Vascular smooth muscle cells and lung parenchyma were also microdissected for clonality studies. RESULTS: The proliferating endothelial cells in 14 plexiform lesions were all polyclonal. Similarly proliferated smooth muscle cells from 5 vessels with medial hypertrophy were also polyclonal. CONCLUSION: These results suggest that the pulmonary hypertension associated with CREST syndrome has different pathogenesis from primary PH and to be classified as secondary PH.