The frequency of antinuclear antibodies (ANA) and other antinuclear factors was prospectively evaluated in patients with sickle cell disease (SCD). Ten of 44 patients studied (22.7%) had positive ANA determinations at titers greater than or equal to 1:40 compared to 3 of 46 healthy controls (6.5%; p less than 0.03). Eight SCD patients had ANA titers of 1:160 or greater compared to none of the controls (p less than 0.003). No antibodies directed against other nuclear factors were found. An analysis of the patient histories revealed no statistical differences between the ANA-positive and ANA-negative SCD patients when correlated with disease activity.