OBJECTIVE: To assess whether the risk of medically attended local reactions to the fifth dose of the diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine varies according to injection site (arm versus thigh). METHODS: We conducted a retrospective cohort study of children aged 4 through 6 years in the Vaccine Safety Datalink population who received a DTaP vaccination during the period from 2002 through 2006. Medically attended local reactions to the DTaP vaccine were presumptively identified from administrative data and were confirmed by medical record review. RESULTS: Among the 233,616 children in the study population, 1017 (0.4%) had a confirmed medically attended local reaction to the fifth dose of the DTaP vaccine. The rate of those reactions was significantly higher with vaccinations given in the arm (47.4 per 10,000 vaccinations) compared with vaccinations given in the thigh (32.1 per 10,000 vaccinations) (P < .001). In a multivariable analysis adjusted for age, gender, and study site, children vaccinated in the arm had a 78% higher risk of a local reaction (relative risk: 1.78 [95% confidence interval: 1.43-2.21]). CONCLUSIONS: Local reactions to the fifth dose of the DTaP vaccine that require medical evaluation are uncommon, but the risk of those reactions is significantly higher when the vaccine is injected in the arm. These findings suggest that the thigh should be considered as an acceptable site of injection for this vaccination.