We previously showed that a single nucleotide polymorphism in S100A4 was associated with portopulmonary hypertension (PPHTN) in patients with advanced liver disease. We aimed to determine the association between plasma levels of S100A4 and PPHTN. We performed a case-control study of patients with advanced liver disease. Cases with PPHTN had mean pulmonary artery pressure >25 mmHg, pulmonary vascular resistance >240 dynes s cm(-5) and pulmonary capillary wedge pressure </=15 mmHg. Controls with liver disease had right ventricular systolic pressure <40 mmHg and normal right atrial and ventricular morphology by echocardiography. Plasma samples were assayed for S100A4. The study sample included 14 cases with PPHTN and 32 controls with liver disease. There was no difference in mean age between cases and controls (p = 0.52). Seventy-nine percent of cases were female compared with 44% of controls (p = 0.03). There was no difference in S100A4 levels between cases and controls (p = 0.58). Both groups had significantly higher S100A4 levels than healthy volunteers (p <0.05). There was no significant difference in plasma levels of S100A4 between PPHTN patients and controls with liver disease, although liver disease itself was associated with increased S100A4 levels.