Retrospective assessment of agricultural workers’ pesticide exposure is essential for understanding and establishing links between their occupational activities throughout their careers and the onset of potential diseases such as cancer or neurodegenerative disorders. Reliable data, generated through a precise and structured method for documenting occupational exposure history, are scarce. Viticulture is among the French crops with the highest pesticide use (2016 treatment frequency index: 15.3), thereby exposing agricultural workers to numerous plant protection products (PPPs). No previous study has identified the number of these workers, the PPPs to which they are and/or have been exposed over time, or linked this exposure to potential health effects that may arise. We used three databases, two of which were developed and co-developed by Santé publique France, to answer the following questions: Which PPPs have been applied in viticulture over the past decades in mainland France? What are their health effects? And what are the characteristics of the affected agricultural worker population? The first database is a crop-exposure matrix (CEM) specific to viticulture, through which we identified all PPPs used on this crop since the 1980s, as well as the frequency and probability of their use. The second data source is the CipaTox database, developed in partnership with the University of Lyon 1. It was established to document the health effects of all active ingredients (AI) in PPPs registered in France since 1961, with a focus on carcinogenic, mutagenic, and reprotoxic potential. Finally, the third source consists of the agricultural censuses (RA) from 1979, 1988, 2000, and 2010, which made it possible to identify the sociodemographic characteristics of vineyard workers. By cross-referencing these three data sources, we calculated the prevalence of occupational exposure to PPPs used in viticulture over the four years of the agricultural census and associated the health effects they may cause. Our study shows that in 1979, 1988, 2000, and 2010, 132 different active ingredients were used in vineyards, including 65 fungicides, 44 insecticides, and 23 herbicides. The main active ingredients, excluding mineral products (copper and sulfur), are folpel, mancozeb, glyphosate, and fenoxycarb. Between 83% (1979) and 72% (2010) of vineyard workers—whose numbers fell from 482,050 (1979) to 162,608 (2010) individuals belonging to the permanent workforce of the farms, were exposed to at least one substance toxic to human health considered to have potentially carcinogenic, mutagenic, or reprotoxic effects within the scope of our study. This research helps guide prevention efforts for agricultural workers by identifying pesticides that may have adverse effects on their health. It encourages the implementation of several measures, including: raising awareness among agricultural workers about the chemical risks associated with pesticide use; promoting alternative methods in viticulture; limiting the use of PPPs; restricting the use of PPPs containing active ingredients that may be considered toxic; wearing personal protective equipment appropriate to weather conditions during treatments; providing information and training to general practitioners and occupational physicians to facilitate the recognition of occupational diseases; and, finally, advancing agricultural equipment, which remains the primary avenue for progress in reducing agricultural workers’ exposure to pesticides.