Pain and acute chest syndrome (ACS) episodes are 2 of the most common causes of hospitalization in children with sickle cell anemia (SCA). However, very few potentially modifiable risk factors for either condition have been identified. In this prospective infant cohort study, we tested the hypothesis that asthma is associated with an increased incidence rate of pain and ACS episodes. An infant cohort was composed of 291 African American children with hemoglobin SS enrolled in the Cooperative Study for Sickle Cell Disease before age 6 months and followed beyond age 5 years. Asthma was defined by a physician diagnosis, an acute asthma event, or use of prescription asthma medications. The incidence rates of ACS and painful episodes were compared for children with and without asthma. A clinical diagnosis of asthma was made in 17% of the cohort. Asthma was associated with more frequent ACS episodes (0.39 vs 0.20 events per patient year, P < .001) and painful episodes (1.39 vs 0.47 events per patient year, P < .001). In conclusion, in children with SCA, asthma is associated with an increased incidence of sickle cell disease-related morbidity, including ACS and painful episodes.