Background: A plant-based dietary pattern has been recently suggested to have health benefits. However, its relationship with mortality is not completely consistent in prior studies. We aimed to investigate whether a plant-based diet was associated with a lower death risk in a Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening study. Methods: We included 91 414 participants from the PLCO study. Dietary data were collected using a diet history questionnaire (DHQ). We used three plant-based diet indices including an overall plant-based diet index (PDI), a healthful plant-based diet index (hPDI), and an unhealthful plant-based diet index (uPDI). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard regression model. Results: During a median of 17.1 years of follow-up, we documented 19 456 deaths, including 5489 deaths from cardiovascular disease (CVD) and 6172 deaths from cancer. Comparing the highest versus lowest quintiles of the PDI, the multivariable-adjusted HR of all-cause mortality was 0.83 (95% CI 0.80-0.87, P for trend < 0.001). Those in the highest quintile of the PDI also had lower risks of CVD mortality (HR 0.87, 95% CI 0.80-0.95, P for trend < 0.001) and cancer mortality (HR 0.89, 95% CI 0.82-0.96, P for trend = 0.003) compared to those in the lowest quintile. Participants in the highest quintile of the hPDI had a decreased risk of all-cause and cause-specific mortality, whereas participants with the highest uPDI scores had an increased death risk. Conclusion: Greater adherence to a plant-based dietary pattern was significantly associated with lower all-cause and cause-specific mortality.