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To address the role of viral load in pathogenesis in patients with hantavirus cardiopulmonary syndrome (HCPS), we quantified Sin Nombre virus S segment viral RNA in plasma samples from 27 acutely-ill patients. For six patients we examined viral load in matched plasma, urine, and/or tracheal aspirate throughout the time when patients were in intensive care. Peak titers in plasma reached 1.8x106 copies/ml; none had viral RNA in urine. Titers in tracheal aspirates did not exceed 8x104/ml. We found a statistically significant association (P< 0.005) between plasma viral RNA levels at admission and the severity of disease. Of those with plasma viral RNA titers above the threshold for assay sensitivity (5000 copies/ml), those with mild-moderate and severe disease had an average of 27,800 and 438,545 copies/ml, respectively. These results suggest that patients with high viral loads on admission are more likely to have severe disease.