Intracutaneous skin tests (STs) and RAST with the common allergens, grass pollen, house dust mite, and cat dander, were performed on 660 adult patients. In 117 patients (18%), we found 140 discordances (7%) in a total number of 1980 ST and RAST combinations. In agreement with studies in the literature, greater than 80% of the discordances consisted of positive skin reactions without detectable allergen-specific IgE antibodies in serum. The percentages of discordant results were similar for the three allergens. Reproducibility of both the RAST and the ST was evaluated in the discordant group. Repetition of the routine RAST procedure elicited results similar to those in the first test in 81% (105/130). A second ST elicited identical results in 89% (47/53). In addition to the routine IgE antibody assay, sera of patients with a positive ST but without detectable IgE antibodies were tested in two other RAST systems: (1) a RAST with allergen extracts from the same production batch as the ST reagents, and (2) the Pharmacia RAST. In spite of having a clearly positive ST, sera from 68 (80%) of 85 patients remained completely negative in all three RAST systems. Histamine release (HR) in vitro from washed leukocytes was studied in 35 patients with a reproducible positive ST and negative RAST results with serum. Interpretation of this test was possible in 28 patients. In 82% (23/28) of these patients, clearly detectable HR was found with the relevant allergen extract. A role of IgE in the skin reactions and HR tests was confirmed by positive RAST results with IgE that was affinity purified from serum of seven of these patients. Allergen-specific IgG4 antibodies are unlikely to be implicated, since no antibodies against grass pollen and house dust mite were detectable in sera of these patients. Only 18% of the patients with an unexplained skin reaction with cat dander have detectable IgG4 antibodies, but these antibodies were found in a similar frequency in a nonallergic, ST negative control group. Low total IgG responses precluded false negative RAST results caused by competition of IgG antibodies with IgE antibodies. There were no significant differences in the degree of complement activation in vitro by house-dust extracts between healthy control subjects, nonallergic patients, and patients with unexplained skin reactivity. It is concluded that a high proportion of the positive skin reactions with common inhalant allergens, which are not accompanied by a positive RAST, are probably caused by IgE antibodies that are not detectable in serum with any of the RAST procedures.(ABSTRACT TRUNCATED AT 400 WORDS)