The major complication of portal hypertension is represented by gastrointestinal haemorrhage from ruptured oesophageal varices. Gold standard prophylaxis with non selective beta-blockers is able to decrease the risk of bleeding or rebleeding only in a fraction of patients, thus additional forms of treatment are under investigation. Long-acting nitrates have been considered the best candidates to improve the pharmacological response. The rationale for the use of nitrates in portal hypertension is primarily based on the fact that they lead to a decrease in the hepatic venous pressure gradient and on the knowledge that deficient intrahepatic nitric oxide release could be one of the mechanisms involved in the development of increased portal resistance in early cirrhosis. Ten randomised controlled trials have, so far, investigated the clinical usefulness of long-acting nitrates in portal hypertension. Five of them explored the field of primary prophylaxis and the others, the use of nitrates in the prevention of rebleeding. The results of these randomised controlled trials are partially contradictory as far as concerns prevention of bleeding or rebleeding, survival and treatment-related complications. A common finding emerging from most of these studies suggests that the potential for a beneficial or detrimental effect of nitrates depends on the stage of liver disease and the extension of portal collaterals. Thus, in the early stage of cirrhosis, it would be desirable to target nitrates to the liver microvasculature, while, in a later stage, nitrates could be deleterious by aggravating the hyperdynamic syndrome through the expansion of the vascular bed. Whether or not nitrates may have a role in the primary and/or secondary prophylaxis of bleeding needs to be addressed in further long-term studies.