To address the role that viral load plays 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 6 patients, we examined viral load in matched plasma, urine, and/or tracheal aspirate throughout the time when the patients were in intensive care. Peak titers in plasma reached 1.8 x 106 copies/mL; none of the patients had viral RNA in urine. Titers in tracheal aspirates did not exceed 8 x 104 copies/mL. We found a statistically significant association (P < .005) between plasma viral RNA levels at admission to the hospital 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.