ABSTRACT: The Gironde estuary has been shown to be the most Cd-contaminated area in France. Oysters Crassostrea gigas of different size classes were sampled from 3 sites between the mouth and 25 km upstream, to study the relative importance of natural andcontamination factors on metal accumulation and metallothionein-like protein (MTLP) induction. The highest metal and MTLP concentrations were observed in the digestive gland. In all organs, the 3 metals were mainly cytosolic. An inverse relationship wasgenerally observed between weight of soft tissues and metals or MTLP concentrations in the whole soft tissues, whereas the influence of weight on metal distribution among cytosolic and insoluble fractions was small. When oysters with similar weight ofsoft tissues were considered, no influence of salinity at different sites was found for Cu and Zn whereas the lowest soluble and insoluble Cd concentrations were observed at the mouth of the river. Salinity did not influence Cu and Zn distribution amongthe cytosolic or insoluble fractions whereas cytosolic Cd in gills and digestive gland (%) was higher at the mouth of the estuary than upstream. MTLP and metal concentrations were generally positively correlated except at those sites where metalconcentrations were lowest. However when multiple regression analyses were performed, weight appeared also as a major or an important factor to explain variations of MTLP levels, the prevalence of this natural factor versus contamination factors beingdifferent at different sites.