Moderate alcohol intake (or, more specifically, red wine) represents one of the postulated beneficial components of the traditional Mediterranean diet. Many well-conducted nonrandomized studies have reported that light-to-moderate alcohol intake is not only associated with reduced risk of cardiovascular disease, but also of all-cause mortality. Nonetheless, alcohol is an addictive substance imposing huge threats for public health. Alcohol consumption is associated with increased risks of cancer, neurological harms, injuries, and other adverse outcomes. Both the Global Burden of Disease (2016) and Mendelian randomization studies recently supported that the healthiest level of alcohol intake should be 0. Therefore, despite findings of conventional observational epidemiologic studies supporting a potential beneficial role of wine in the context of a healthy Mediterranean dietary pattern, a strong controversy remains on this issue. Age, sex, and drinking patterns are likely to be strong effect modifiers. In this context, a new 4-y noninferiority pragmatic trial in Spain (University of Navarra Alumni Trialist Initiative or "UNATI"), publicly funded by the European Research Council, will randomly assign >10,000 current drinkers (males, 50-70 y; females, 55-75 y) to repeatedly receive advice on either abstention or moderation in alcohol consumption. The recruitment will begin in mid-2024. The primary endpoint is a composite of the main clinical outcomes potentially related to alcohol intake including all-cause mortality. Clinical trial registry number: PREDIMED, ISRCTN35739639, www.predimed.es; SUN, clinicaltrials.gov identifier: NCT02669602, https://medpreventiva.es/i2CmeL.