The impact of dispersed crude oil and dispersant on adult Pacific oysters, Crassostrea gigas, was evaluated through an integrative biomarker approach including (1) biochemical (plasma catecholase- and laccase-type phenoloxidase and superoxide dismutase), (2) histological (digestive cell lysosomal responses, digestive gland histopathology) and (3) physiological (flesh condition index) endpoints in the haemolymph and digestive gland. Adult oysters were exposed to non-contaminated water (control), chemically-dispersed oil (Brut Arabian Light), mechanically-dispersed oil and dispersant (FINASOL®) alone for 2 days, and further depurated in noncontaminated water for 4 weeks. After exposure to chemically and mechanically dispersed oil oysters exhibited induction of plasma laccase-type phenoloxidase and superoxide dismutase activities, enlargement of digestive cell lysosomes, lipofuscin accumulation, reduced neutral lipid content and atrophy of digestive gland diverticula; more markedly on exposure to chemically dispersed oil. From the studied biomarkers, only lysosomal biomarkers were significantly affected after exposure to the dispersant alone. This included lysosomal enlargement, neutral lipid depletion and lipofuscin accumulation in the digestive gland epithelium. A recovery of plasma enzyme activities was observed after 4 weeks of depuration. The integrative biological response index indicated that chemically dispersed oil caused significantly higher stress to C. gigas than the mechanically-dispersed one or the dispersant alone; nevertheless, the response seems to be reversible after depuration.