Background During the initial phases of the vaccination campaign worldwide, nonpharmaceutical interventions (NPIs) remained pivotal in the fight against the COVID-19 pandemic. In this context, it is important to understand how the arrival of vaccines affected the adoption of NPIs. Indeed, some individuals might have seen the start of mass vaccination campaigns as the end of the emergency and, as a result, relaxed their COVID-safe behaviors, facilitating the spread of the virus in a delicate epidemic phase such as the initial rollout. Objective The aim of this study was to collect information about the possible relaxation of protective behaviors following key events of the vaccination campaign in four countries and to analyze possible associations of these behavioral tendencies with the sociodemographic characteristics of participants. Methods We developed an online survey named “COVID-19 Prevention and Behavior Survey” that was conducted between November 26 and December 22, 2021. Participants were recruited using targeted ads on Facebook in four different countries: Brazil, Italy, South Africa, and the United Kingdom. We measured the onset of relaxation of protective measures in response to key events of the vaccination campaign, namely personal vaccination and vaccination of the most vulnerable population. Through calculation of odds ratios (ORs) and regression analysis, we assessed the strength of association between compliance with NPIs and sociodemographic characteristics of participants. Results We received 2263 questionnaires from the four countries. Participants reported the most significant changes in social activities such as going to a restaurant or the cinema and visiting relatives and friends. This is in good agreement with validated psychological models of health-related behavioral change such as the Health Belief Model, according to which activities with higher costs and perceived barriers (eg, social activities) are more prone to early relaxation. Multivariate analysis using a generalized linear model showed that the two main determinants of the drop of social NPIs were (1) having previously tested positive for COVID-19 (after the second vaccine dose: OR 2.46, 95% CI 1.73-3.49) and (2) living with people at risk (after the second vaccine dose: OR 1.57, 95% CI 1.22-2.03). Conclusions This work shows that particular caution has to be taken during vaccination campaigns. Indeed, people might relax their safe behaviors regardless of the dynamics of the epidemic. For this reason, it is crucial to maintain high compliance with NPIs to avoid hindering the beneficial effects of the vaccine.