In the United States, sickle cell anemia (SCA) affects approximately 1 in 400 African-American newborns. Acute episodes of pain and acute chest syndrome (ACS) are the two leading causes of hospitalization. A relationship between the diagnosis of asthma and the incidence of pain and ACS has been established. We tested the hypothesis that a familial pattern of inheritance of asthma exists among first degree relatives of probands with SCA and asthma. Segregation analysis was performed in 104 families ascertained through affected probands. Of these, 19.7% (41/208) of the parents and 31.8% (28/88) of siblings of affected probands reported having been told by a doctor he or she had asthma at any age. Modes of inheritance were tested, using the Pedigree Analysis Package parameterized for the discrete trait of asthma affection status. A major effect was present and significant. Further tests were performed to determine whether transmission probabilities of the major effect followed Mendelian expectations. The additive mode of inheritance was the most parsimonious, while the residual heritability was found negligible. Our results support the hypothesis that a familial pattern of inheritance of asthma exists among first degree relatives of probands with SCA and asthma, suggesting that asthma is a co-morbid condition with SCA rather than a lung disease phenotype mimicking asthma.