The hygiene hypothesis proposes that declining exposure to infections may contribute to the allergy and asthma "epidemic", but studies to identify the infections involved have so far provided conflicting data. An alternative approach could be based on an attempt to identify the mechanisms common to several different infections, which may exert an atopy "protective" effect. One of these mechanisms may be fever, which is frequently associated with infections and may stimulate the synthesis of interferon-gamma. The aim of this study was to test whether the frequency of fever episodes in the first years of life are related to the development of atopy. Asthmatic (cases, n=317) and nonasthmatic children (controls, n=304) attending the outpatients' allergy clinic were enrolled. The number of fever episodes in the first 2 yrs of life was retrospectively assessed by parental report via a questionnaire completed by interview. Atopy was determined by skin-prick tests to 10 prevalent inhalant allergens at the time of examination. Fever episodes in the first or in the second year of life were significantly more frequent among children with asthma. However, this difference was totally accounted for by a subgroup of children who started wheezing in the first 12 months of life. A significant inverse association between fever episodes in the first 12 months of life and atopy was found among cases, but not in controls. The association persisted after adjusting for age, sex, daycare attendance and family history of atopic disease and this was totally accounted for by asthmatic children who started wheezing after the first 12 months of life. No significant association was found between fever episodes in the second year of life and atopy for cases and controls. The data presented here suggests that fever episodes early in life may affect the natural history of asthma by preventing the development of atopy and highlights the need to monitor fever episodes of any kind in longitudinal studies aimed at investigating the hygiene hypothesis prospectively.