Angiotensin-converting enzyme (ACE) inhibitors are one of the first drugs of choice for the treatment of hypertension. However, there have been many reports of persistent chronic dry cough and inflammatory skin reactions (rash and/or angioedema, etc.) induced by ACE inhibitors. In this study, in order to evaluate the cough and inflammatory reaction, we measured the number of citric acid-induced coughs and the intradermal inflammation with ovalbumin in guinea pigs consecutively treated with ACE inhibitors (lisinopril, enalaprilat and imidapril) for 3 days. The number of citric acid-induced coughs and the inflammatory responses were significantly enhanced by treatment with lisinopril and enalaprilat, whereas imidapril produced no change in either response. These results correspond to the frequency of adverse effects in clinical practice, which suggests that imidapril has the least ability to induce the inflammatory skin response and cough. Furthermore, the enhancement produced by the ACE inhibitors in the number of coughs and the inflammatory responses were significantly reduced by pretreatment with indomethacin (prostaglandin synthesis inhibitor). This finding suggests that PGs at least participate in the mechanism for ACE inhibitor-induced cough and inflammatory skin response.