Abstract Seven subjects, who experienced systemic allergic reactions after the ingestion of a newly marketed food supplement, were evaluated to identify the responsible ingredient. Skin testing with extracts prepared from ingredients in the food supplements revealed marked sensitization of all of the subjects to cottonseed protein. Double-blind, placebo-controlled food challenges performed in two subjects with cottonseed flour produced reactions consisting of oropharyngeal pruritus, rhinitis, nausea, diaphoresis, dyspnea, cough, and a fall in pulmonary function tests of 45% or more. All placebo challenges were negative. Because of the reactions observed during these challenges, other subjects were not challenged orally with cottonseed protein but consumed without incident other ingredients in the supplement to which they were skin test positive. Our evaluation strongly incriminates cottonseed protein as the cause of the systemic allergic reactions in these subjects and is consistent with earlier articles in the literature describing the potent allergenicity of cottonseed protein.