Using a new sequential analytic method, the safety of tetanus-diphtheria-acellular pertussis (Tdap) vaccine was monitored weekly among subjects aged 10-64 years during 2005-2008. Encephalopathy-encephalitis-meningitis, paralytic syndromes, seizures, cranial nerve disorders, and Guillain-Barré syndrome were selected as outcomes based on previous reports and biologic plausibility. The risk following Tdap was not significantly higher than the risk after Td. Statistical power was sufficient to detect a relative risk of 4-5 for Guillain-Barré syndrome and 1.5-2 for the other outcomes. This study provides reassurance that Tdap is similar in safety to Td regarding the outcomes studied and supports the viability of sequential analysis for post-licensure vaccine safety monitoring.