Pulmonary veno-occlusive disease (PVOD) is an uncommon form of unexplained (primary) pulmonary hypertension (PPH) rarely diagnosed during life and generally associated with a progressively deteriorating course. We describe three patients with PVOD; in two of them, diagnosis was established by open lung biopsy. All three patients underwent right heart catheterization and acute vasodilator testing, and each responded favorably to at least one test agent. One patient did not receive chronic vasodilator therapy and died seven months after his initial evaluation. The other two patients were treated with chronic vasodilator therapy; one initially improved, but then experienced progressive right heart failure and died 23 months after the start of therapy, the third patient is alive and clinically improved 72 months after beginning vasodilator therapy. Details of the vasodilator studies, and the rationale for treating this uncommon disorder, are provided.