A hydroponic experiment was carried out to investigate the effect of cadmium (Cd) on differential expression, oxidative stress and some antioxidant enzyme activities in two Lactuca sativa cultivars (Balady, related Romaine Group and Great leaks, related Crisp Group). Cd phytotoxicity was shown by growth retardation of Balady and Great leaks. Results showed that Great leaks showed more sensitivity to Cd toxicity than Balady cultivar. Increasing Cd supply markedly reduced the total chlorophyll, dry matter of both Lactuca cultivarsand these decreases were more marked in great leaks. Increased Cd accumulation in various plant parts in both the Lactuca cultivars was observed as Cd concentration increased. Cd accumulated in the roots was much higher than in the shoot in the two cultivars, but more observed in the case of Balady cultivar. Balady cultivar had less uptake of Cd by shoot about two times than Great leaks shoot cultivar indicating that there are co-ordination of gene expression, regulation ion transport process operating in different root layer more efficient in Balady cultivar compared with Great leaks. Moreover, the induction of expression and activities of antioxidant enzymes and non protein thiol (NPT) increased in Balady cultivar more than Great leaks leading to H₂O₂ burst, lipid peroxidation, and growth inhibition. These gene expression and activities of antioxidant enzymes confer Balady cultivar some measure of Cd tolerance and presence of strong Cd-binding proteins in the roots. In conclusion, these results may be regarded as an indication of better tolerance mechanism of Balady cultivarmore than that of Great leaks to Cd contamination.