Hydroxyurea is the only medication shown to reduce the severity of sickle cell disease (SCD), but its long-term risks are unknown. Families of 58 children with SCD were interviewed on their perception of the potential risks of hydroxyurea treatment, and whether disease severity was a major factor in their treatment decision. Parents rated the severity of their child's SCD (86% as severe, 26% moderate, and 47% mild) and then the highest levels of risk that they would tolerate for both potential cancer (range 1/1,000 to 1/2) and potential birth defects (range 1/1,000 to 1/3) to benefit their child with hypothetical hydroxyurea treatment. Parents of 29 of the 58 children were unwilling to take any cancer risk whatsoever as a potential side effect of treatment, and 29 of 58 (not all the same parents) were unwilling to take any risk for birth defects, including half the children with severe SCD. For those families who did accept some risk, higher acceptable risk correlated with higher disease severity in the child (P = 0.04). The study's mixed findings highlight the complexities of risk perception and suggest that future studies of risks and benefits from the parental viewpoint are needed as candidate therapies are developed for SCD.