Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM. We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine. Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5-28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5-28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2-471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, -.04 to 1.16) cases per million doses. We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.