Major life events are often discussed as triggers of loneliness. However, longitudinal studies with frequent assessments investigating changes in loneliness surrounding major life events are lacking. This preregistered study investigated the associations between various family- and work-related major life events and changes in loneliness, using propensity-score matched data from a Dutch nationally representative prospective longitudinal study. We applied mixed-effects models to describe average loneliness trajectories before, during, and after 10 major life events. Event-related loneliness trajectories differed between events and individuals. Most changes in loneliness were found in reaction to family-related major life events. We found immediate and long-lasting increases in loneliness after the transition into parenthood, marital separation, widowhood, but also after a job loss. Further gradual changes in loneliness were found after marriage, marital separation, and job loss. On average, transition into paid employment, reemployment after unemployment, retirement, and cohabitation did not trigger changes in loneliness. For some major life events, we found that event-related loneliness trajectories differed between individuals who experienced an event at an average age and individuals who experienced an event younger or older than average. Overall, our results highlight the importance of considering major life events as possible triggers of loneliness but also point to some general methodological challenges when studying the effects of major life events. (PsycInfo Database Record (c) 2021 APA, all rights reserved).