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The rising incidence of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup W in Western Australia, Australia, presents challenges for prevention. We assessed the effects of a quadrivalent meningococcal vaccination program using 2012–2020 IMD notification data. Notification rates peaked at 1.8/100,000 population in 2017; rates among Aboriginal and Torres Strait Islander populations were 7 times higher than for other populations. Serogroup W disease exhibited atypical manifestations and increased severity. Of 216 cases, 20 IMD-related deaths occurred; most (19/20) were in unvaccinated persons. After the 2017–2018 targeted vaccination program, notification rates decreased from 1.6/100,000 population in 2018 to 0.9/100,000 population in 2019 and continued to decline in 2020. Vaccine effectiveness (in the 1–4 years age group) using the screening method was 93.6% (95% CI 50.1%–99.2%) in 2018 and 92.5% (95% CI 28.2%–99.2%) in 2019. Strategic planning and prompt implementation of targeted vaccination programs effectively reduce IMD.