Renal acidification was evaluated in patients with sickle-cell disease (HbSS) with both oral NH4Cl and NaHCO3 and the results were compared to those of subjects with sickle-cell trait (HbAS) and controls. The pH of arterial blood was normal in HbSS subjects but their PCO2 [CO2 tension] and [HCO3] were lower than those of controls. In response to NH4Cl, 6 of 20 NbSS subjects had an abnormal minimal urine pH (greater than 5.3) and the entire HbSS group had a higher mean value than did either controls or HbAS subjects. Since none of the 6 HbSS subjects had evidence of proximal tubular abnormalities, it was concluded that they exhibited the syndrome of incomplete distal renal tubular acidosis. Only 1 of the 6 HbSS volunteers with an abnormal response to NH4Cl and 2 of 7 with a normal response increased their urinary PCO2 normally after bicarbonate loading. PAH [p-aminohippurate] clearance was significantly higher and inulin clearance tended to be higher in HbSS subjects than in either controls or HbAS subjects. Maximal concentrating ability was decreased in both sickle-cell groups but more so in HbSS. No adverse effects occurred and no appearance or increase in percent of sickled cells resulted from short-duration NH4Cl acid-loading. No differences were found either in the clinical characteristics or in hematological, renal and acid-base variables between the HbSS subjects with and without a normal response to acid-loading. The mechanism for the observed renal acidification abnormality remains unknown.