No data exist on the associations of dietary tomato and lycopene consumption with total and cause-specific mortality. Using the National Health and Nutrition Examination Surveys (NHANES) 1999-2010, we evaluted the long-term impact of tomato and lycopene intake on total and cause-specific (coronary heart disease [CHD] and cerebrovascular disease) mortality. We also assessed the changes in cardio-metabolic risk factors according to tomato and lycopene intake. Vital status through December 31, 2011 was ascertained. Cox proportional hazard regression models (followed by propensity score-matching) were used to investigate the link between tomato and lycopene consumption total, CHD and cerebrovascular mortality. Among the 23,935 participants included (mean age = 47.6 years, 48.8% men), 3403 deaths occurred during 76.4 months of follow-up. Tomato intake was inversely associated with total (risk ratio (RR):0.86, 95% confidence interval (CI):0.81-0.92), CHD (0.76, 95%CI: 0.70-0.85) and cerebrovascular (0.70, 95%CI: 0.62-0.81) mortality. Similar inverse associations were found between lycopene consumption, total (0.76, 95%CI: 0.72-0.81), CHD (0.73, 95%CI: 0.65-0.83) and cerebrovascular (0.71, 95%CI: 0.65-0.78) mortality; these associations were independent of anthropometric, clinical and nutritional parameters. Age and obesity did not affect the associations of tomato and lycopene consumption with total, CHD and cerebrovascular mortality. C-reactive protein significantly moderated the link between lycopene and tomato intake with total, CHD and cerebrovascular mortality. Analysis of co-variance showed that participants with a higher tomato and lycopene consumption had a more cardio-protective profile compared with those with a lower intake. Our results highlighted the favorable effect of tomato and lycopene intake on total and cause-specific mortality as well as to cardio-metabolic risk factors. These findings should be taken into consideration for public health strategies.