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We evaluated the incidence of allergic and vasomotor symptoms, serum IgE concentrations, and the cutaneous responses to allergens and/or methacholine in 229 Waorani Indians residing at 300 m altitude near the headwaters of the Amazon River, 39 Tibetans residing at 4000 m in the Himalayas, and 84 healthy subjects residing at 150 m in the piedmont region of North Carolina. The Waorani Indians had a high level of intestinal parasitism, an intermediate level of parasitism occurs in Tibetans, and parasitism is rare in the control population. One Waorani Indian (less than 1%), six Tibetans (15%), and 59 North Carolina subjects (88%) had a past history of allergic or vasomotor symptoms. The prevalence of positive epicutaneous allergen skin tests among the Waorani was 40 in 2910 tests and was significantly less (chi-squared = 184.5; p less than or equal to 0.0001) than the 151 in 1344 incidence in the North Carolina subjects. Large highly significant differences (p less than or equal to 0.0001) were detected between the geometric mean IgE concentrations (international unit per milliliter) and methacholine-induced cutaneous flare responsiveness (millimeter) elicited, respectively, in comparisons between the Waorani Indians (9806 IU/ml; less than 1.0 mm), Tibetans (2930 IU/ml; 2.06 mm), and North Carolina subjects (108 IU/ml; 4.49 mm). Differences in methacholine sensitivity were small and not significant. A highly significant inverse relationship (r = -0.50, p less than or equal to 0.0001) was detected between the circulating IgE concentrations and the methacholine-induced cutaneous flare responsiveness in this cross-cultural, cross-environmental comparison of three populations.(ABSTRACT TRUNCATED AT 250 WORDS)