Parthenium hysterophorus (PH) is a ubiquitous weed found in the U.S. Gulf Coast. In this study, 582 sera, contributed by 22 physicians from 18 Gulf Coast cities, were examined by ELISA for IgE directed against determinants in an aqueous extract of PH pollen, and these were compared to an extract of western ragweed (Ambrosia psilostachya [AP]). Overall, 65.6% of the sera tested were positive for one or both of the pollen extracts examined. Thirty-five percent of the sera were sensitive to PH and 57.6% were sensitive to AP. Thirty percent of the sera were positive to AP only, 8.0% were positive to PH only, and 27.9% of the sera were positive to both extracts. ELISA-inhibition analysis demonstrated that PH and AP extracts contained unique allergenic epitopes. Clinical correlation of in vitro reactivity with skin testing and patients' symptoms confirmed that PH sensitivity by ELISA was related in many cases to fall seasonal symptoms. These data demonstrate by in vitro analysis the presence of IgE directed against an extract of PH pollen in a significant number of patients with fall seasonal pollinosis in the U.S. Gulf Coast. Thus, allergic reactivity to PH may be a significant contributor to fall allergic disease in the U.S. Gulf Coast.