Rationale: Monge's disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high altitude dwellers. It has a considerable impact on public health in high altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (250 mg/day for 3 weeks) in reducing serum erythropoietin and hematocrit. Objectives: Evaluate the efficacy and tolerance of a 6-month treatment with 250 mg acetazolamide that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function. Methods: A two-phase study was performed in patients (hematocrit 63%) from Cerro de Pasco, Peru (4,300 m). First phase: a double blind placebo-controlled study in 55 patients who receive a single dose of either 250mg acetazolamide (n=40) or placebo (n=15) by daily oral administration for twelve weeks. Second phase (open label): after a four-week wash out period, all patients received 250mg acetazolamide for twelve weeks. Hematocrit, blood gases, clinical outcome and pulmonary artery circulation were evaluated. Results: First phase: acetazolamide decreased by 44% the number of polycythemic subjects (p=0.02), decreased hematocrit from 69 to 64% (p<0.001) and increased arterial O₂ pressure from 42 to 45 mmHg (p<0.001). No severe adverse effect, nor hypokalemia was recorded. The second phase reproduced the effects observed during the first phase, without cumulative effects on hematocrit. A four-week washout restored basal hematocrit. Only patients who received Acz for 6 months showed a clear reduction in pulmonary vascular resistance. Conclusions: Acetazolamide reduces erythrocytosis and improves pulmonary circulation in Monge's disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe. Registered at www.clinicaltrials.gov, ID# NCT00424970