Influenza is known to be associated with asthma exacerbation but the effectiveness of the trivalent inactivated flu vaccine (TIV) in children, especially children with asthma, in preventing hospitalization is unknown. We assessed the effectiveness of the TIV in all children and especially children with asthma to prevent hospitalization with influenza. We conducted a nested case control study of all pediatric subjects (6 months to 18 years old) who were evaluated at the Mayo Clinic, Rochester, MN, who had laboratory-confirmed influenza during each flu season from 1999 to 2006 to evaluate the efficacy of TIV in preventing hospitalization. A case-control analysis was performed with the cases and the controls being the subjects who did and did not required hospitalization with the influenza illness, respectively. There were 261 subjects with laboratory-confirmed influenza from 1996 to 2006. There was an overall trend toward higher rates of hospitalization in subjects who got the TIV when compared with the ones who did not get the TIV (odds ratio [OR], 3.67; CI, 1.6, 8.4). Using the Cochran-Mantel-Haenszel test for asthma status stratification, there was a significant association between hospitalization in asthmatic subjects and TIV (p = 0.001). TIV did not provide any protection against hospitalization in pediatric subjects, especially children with asthma. On the contrary, we found a threefold increased risk of hospitalization in subjects who did get the TIV vaccine. This may be a reflection not only of vaccine effectiveness but also the population of children who are more likely to get the vaccine.