Background: Individuals diagnosed with nonmelanoma skin cancer have a high risk of developing a second skin cancer diagnosis. We assessed whether a marker of immune function related to atopic allergy, IgE, was associated with diagnosis of subsequent squamous cell carcinoma (SCC) of the skin in patients with a previous skin cancer enrolled in a skin cancer prevention trial. Methods: One hundred twelve individuals who developed an SCC (cases) were compared with 227 controls who did not develop SCC over the same followup period, matched on age, sex, and study center. Total, respiratory, and food-specific IgE were measured in the baseline or year one (prior to diagnosis) sera samples for each subject. Results: IgE levels were higher in cases with SCC than controls (comparing the highest quartile with the lowest, OR total IgE = 1.44; 95% CI: 0.73-2.85; OR respiratory IgE = 2.43; 95% CI: 1.16-5.06; OR food IgE = 2.53; 95% CI: 1.19-5.35). The association between respiratory IgE and subsequent skin cancer was strongest among individuals with a tendency to sunburn (OR respiratory IgE = 3.82; 95% CI: 1.05-13.88) compared with those with a tendency to tan (OR respiratory IgE = 0.95; 95% CI: 0.20-4.76). Among 25 subjects with repeat IgE measurements taken over several years, IgE levels were remarkably stable (interclass coefficient = 0.90 for total IgE). Conclusion: These results indicate that allergy or allergy-associated IgE may be indicative of an immune phenotype that enhances risk of SCC, possibly via immune-associate inflammatory mediators. Impact: Our results indicate that controlling allergy and IgE levels may be a new avenue of skin cancer prevention in susceptible populations, and implicate immune mechanisms in skin carcinogenesis.