The elevation of tumor markers in benign diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, or diabetes mellitus has been reported recently. We had the opportunity to observe a female patient with progressive systemic sclerosis (PSS) and pleuritis who demonstrated a high level of CA125 in her pleural effusion and blood serum. The purpose of this report is to describe this case. We also investigated whether tumor markers are elevated in collagen disease. We measured the serum levels of CA125 and CA19-9 in our case of PSS with pleuritis, 27 female patients with collagen diseases including SLE, PSS, dermatomyositis and Sjögren syndrome, and 11 normal females as controls. Compared with the normal controls, there was no evident elevation of CA19-9 or CA125 levels in collagen diseases except in our case. Elevated serum CA125 may be one of the indicators of pleural effusion in collagen disease.