Regeneration experiments in Hydra have shown that lithium long-term treatment apparently causes a transformation of prospective head into foot tissue. Although lithium ions are known to interfere with the PI-PKC signal-transduction system and evidence has been provided that this system plays a role in pattern formation in Hydra, its role in mediating the lithium effect on patterning is still obscure. The present study provides evidence that H2O2 and presumably also lipid hydroperoxides mediate the lithium effects. First, the perturbation of pattern formation is strikingly stronger in the strain Hydra vulgaris than in Hydra magnipapillata, and similar strain-specific differences are found in the long lasting accumulation of hydroperoxides following lithium treatment. Second, the antioxidant vitamins E and C, which suppress peroxide accumulation, and the H2O2-degrading enzyme catalase significantly protect H. vulgaris from lithium effects. Lithium treatment also negatively affects overall DNA synthesis in a similar strain-specific manner, which, however, cannot be rescued by antioxidant vitamins. The lithium-activated source of peroxide production differs from another source, which generates peroxide in untreated polyps of both strains. The results suggest that lithium treatment-induced peroxide accumulation in H. vulgaris provokes a cytotoxic response showing foot-like characteristics. Nevertheless, a role of peroxides as messengers in pattern forming processes can not be excluded.