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BACKGROUND We recently reported a more rapid waning of vaccine-induced humoral immunity (measles vaccine) in children with asthma. It is unknown if asthma affects susceptibility to vaccine-preventable diseases. OBJECTIVE To determine whether asthma is associated with an increased risk of vaccine-preventable disease, e.g., breakthrough varicella infection. METHODS This was a retrospective population-based case-control study that examined cases of breakthrough varicella among children between 2005 and 2011. Children with a diagnosis of breakthrough varicella infection in Olmsted County, Minnesota (infection of >42 days after vaccination) between 2005 and 2011 and two age- and sex-matched controls were enrolled for each case. Asthma status was determined by using predetermined criteria. Conditional logistic regression models were used to calculate matched odds ratios (OR) and their corresponding 95% confidence intervals (CI). RESULTS Of the 165 cases and their 330 matched controls, 48% were boys and the mean (standard deviation) age at the index date was 6.6 ± 3.5 years for both cases and controls. Of the 330 controls, 80 (24%) had two doses of the varicella vaccine compared with only 23 (14%) of the 165 cases (OR 0.29 [95% CI, 0.14-0.61]; p = 0.001). Children with a history of asthma ever had a higher risk of developing breakthrough varicella compared with those without a history of asthma (adjusted OR 1.63 [95% CI, 1.04-2.55]; p = 0.032) when adjusting for elapsed time since the first varicella vaccination and the number of varicella vaccine doses. CONCLUSIONS A history of asthma might be an unrecognized risk factor for breakthrough varicella infection. Children with asthma should follow the two-dose varicella vaccine policy.