Two cases of interstitial pneumonia with cardiac failure developing in patients treated with the new antidepressant venlafaxine are presented. A strong relationship between the development of the patients' illness and the initiation of venlafaxine treatment was identified. The cytochrome P (CYP) 450 system is involved in the metabolism of venlafaxine, suggesting that alterations in the drug metabolic clearance might be, at least in part, responsible for the development of drug-induced damage in these cases. This might occur either as a consequence of a genetic factor or concomitant drug therapy with an inhibitor of the related CYP system. After identifying the causative agent in the first case, withdrawal of the antidepressant together with corticosteroid treatment led to a favorable outcome. In the other case, the multiorgan failure became fatal. These cases highlight a hitherto undescribed association of an adverse lung reaction and heart failure due to venlafaxine.