Following the identification of a cluster of lead poisoning in western French Guiana in 2011 and the implementation of a lead poisoning control plan by the Regional Health Agency, Santé publique France was commissioned to conduct a study on lead exposure among children aged 1 to 6 years, with the aim of determining the prevalence of lead poisoning and identifying its determinants. The survey was conducted in 2015–2016 in the department’s three hospitals as well as in decentralized prevention and care centers in remote areas. A total of 590 children were included, allowing the prevalence of lead poisoning (blood lead levels ≥50 µg/L) to be estimated at 20.1% and the average (geometric) blood lead level at 22.8 µg/L. Both figures were significantly higher than the values observed in metropolitan France in 2008–2009 in the Saturn-inf study. The analysis of the determinants of blood lead levels was conducted using a generalized linear model. Thus, the main risk factors for blood lead levels among children aged 1 to 6 years in French Guiana are living along rivers, spending 7 hours or more outdoors per day, consuming couac and wassaï, or being a heavy rice consumer. These results are consistent with those of environmental surveys conducted since 2011 and various measurements taken in soil and food. They suggest a multifactorial exposure primarily through diet, occasionally exacerbated by contamination of food crop soils. They should be supplemented by further studies incorporating isotopic analyses to trace the sources of this metal in various food compartments or certain behaviors (hunting, fishing), as well as its transfer from soil to plants, with a view to reducing the population’s risk of lead exposure.