AbstractIn early May 2022 a global outbreak of monkeypox (MPX) started among persons without a travel history to regions known to be enzootic for monkeypox-virus. On August 8 2022, the Netherlands reported its 1000thmonkeypox case representing a cumulative incidence of 55 per million population, one of the highest cumulative incidences worldwide. Here we describe the epidemiological characteristics and clinical presentation of the first 1000 monkeypox cases in the Netherlands, within the context of the public health response. Additionally, we explored risk factors for and estimated the protective effect of first-generation smallpox vaccine against more severe MPX.The first 1000 MPX cases, reported between May 20 and August 8 2022, were predominantly MSM aged 31-45 years. The vast majority of infections were acquired through sexual contact with casual partners in private or recreational settings including LGBTQIA+ venues in the Netherlands. This indicates that, although some larger upsurges occurred from point-source and/or travel related events, the outbreak is mainly characterised by sustained transmission within the Netherlands. More severe MPX was associated with having one or more comorbidities as well as having participated in more (3+) different sexual activities 21 days before symptom onset. We found a vaccine effectiveness of the prior first-generation smallpox vaccine against more severe MPX of 58% (95% CI 17-78%), suggesting moderate protection against more severe MPX symptoms on top of any possible protection by this vaccine against MPXV infection and disease.