Asthma is a phenotypically heterogeneous disease. Two subgroups are defined here based initially on skin test reactivity to the allergen Alternaria at age 6 from among a large population of children born and raised in the Southwestern desert environment of Tucson, Arizona. When compared with asthma among Alternaria-positive subjects, asthma among Alternaria-negative subjects was associated with lower levels of total serum IgE, no relation to local aeroallergen skin tests, a younger age at diagnosis, greater remittance by age 11, and more frequent wheezing lower respiratory illnesses (LRIs) in the first year of life. Despite the difference in total serum IgE, however, IgE concentrations were significantly higher in each asthma group compared with its respective control group. Asthma in each parent contributed approximately equivalent risk for Alternaria-positive asthma in the child. However, neither parental skin test sensitization nor total serum IgE levels provided risk for asthma in the child. Inheritance patterns for Alternaria-negative asthma revealed a contribution from maternal but not paternal asthma. Thus, dividing asthma in children at age 6 into Alternaria-positive and Alternaria-negative groups identifies subphenotypes that are further distinguished by differences in phenotypic markers and parental influences.