Over the last few years, a pivotal role has been ascribed to reduced nitric oxide (NO) availability as a contributing factor to the vaso-occlusive process of sickle cell disease. We investigated whether arginine metabolism in sickle cell patients is different from healthy controls. Blood samples were drawn by venipuncture in the fasting state from 8 clinically asymptomatic HbSS patients and 14 race-matched HbAA controls. HbSS patients had decreased plasma arginine (p=0.001) and increased proline (p=0.015) levels as compared to controls. Ratios of arginine to ornithine (p<0.001), proline (p<0.001), glutamate (p=0.003), and citrulline (p=0.026) were lower in HbSS patients. There were significant correlations of ornithine (r(s)=-0.71, p=0.047), citrulline (r(s)=-0.79, p=0.021), arginine/ornithine (r(s)=0.93, p=0.001), and arginine/citrulline (r(s)=0.81, p=0.015) to hemoglobin and of arginine/proline (r(s)=-0.76, p=0.028) and citrulline (r(s)=0.71, p=0.048) to leukocyte counts. These data indicate that in clinically asymptomatic sickle cell patients increased arginine metabolism is shifted to the arginase pathway and that this seems to be more profound in patients with higher hemolytic rates and leukocyte counts.