AimThis study aims to fill a research gap in the literature on assessing the effectiveness of non-pharmaceutical interventions (NPIs) in the SARS-CoV-2-pandemic by conducting a natural experiment with a no-treatment control group. The effectiveness of five NPIs is tested, with the German state Baden-Wurttemberg being the intervention group, and adjacent Switzerland being the control group.Subject and methodsFive NPIs in the second SARS-CoV-2 wave (autumn/winter 2020/21) are tested to see whether they cause a reduction in the effective reproduction number of infections, namely the closures of daycare facilities, primary and secondary schools, hotels, and close-contact services. The statistical analysis is conducted using a difference-in-differences approach. Several control variables are included in the regression model. To check the robustness of the results, several models with differently backdated infections are estimated.ResultsThe closure of close-contact services (e.g., hairdressers) caused a reduction in the effective reproduction number of approximately 1.7%, i.e., reduced infections. The closure of daycare facilities, schools, and hotels does not have a significant dampening effect on the effective reproduction number.ConclusionOf five NPIs examined, only one is demonstrably effective. If measures are not effective, it is questionable whether they should be implemented at all. When assessing NPIs, greater attention should be paid to methodological aspects, particularly with respect to conducting natural experiments, the inclusion of control variables in the regression models to quantify NPI effects, and the backdating of infection cases.