Background: The association between childhood vaccinations and infections and risk of multiple sclerosis is unclear; few studies have considered age at vaccination/infection. Objective: To explore age-related associations between childhood vaccinations, infection and tonsillectomy and risk of a first clinical diagnosis of CNS demyelination. Methods: Data on case (n = 275, 76.6% female; mean age 38.6 years) and age- and sex-matched control (n = 529) participants in an incident population-based case-control study included self-reported age at time of childhood vaccinations, infections, and tonsillectomy. Conditional logistic regression models were used to calculate adjusted odds ratios (AOR) and 95% confidence intervals (CI). Results: Poliomyelitis vaccination prior to school-age was associated with increased risk of a first clinical diagnosis of CNS demyelination (AOR = 2.60, 95%CI 1.02–6.68), based on a very small unvaccinated reference group. Late (11–15 years) rubella vaccination (compared to none) was associated with lower odds of being a case (AOR = 0.47, 95%CI 0.27–0.83). Past infectious mononucleosis at 11–15 years (AOR = 2.84, 95%CI 1.0–7.57) and 16–20 years (AOR = 1.92, 95%CI 1.12–3.27) or tonsillectomy in adolescence (11–15 years: AOR = 2.45, 95%CI 1.12–5.35), including after adjustment for IM, were associated with increased risk of a first clinical diagnosis of CNS demyelination. Conclusions: Age at vaccination, infection or tonsillectomy may alter the risk of subsequent CNS demyelination. Failing to account for age effects may explain inconsistencies in past findings.