The aim of the present work is to comparatively evaluate the oxidative stress response on exposure to natural organic matter (NOM) in three amphipod (Crustacea, Amphipoda) species from different taxonomic groups and different habitats of Lake Baikal. Endemic species from Lake Baikal were used: the shallow-water dwelling Gmelinoides fasciatus (Dyb.), Pallasea cancelloides (Gerstf.), and the deep-layer inhabitant Ommatogammarus flavus (Dyb.). Three key enzymes, catalase (CAT), peroxidase (POD), and glutathione S-transferase (GST), were studied. The applied NOM from Lake Schwarzer (Germany) directly impacts the two littoral species which quickly respond. The response is characterized by a significant decrease of POD and an increase of CAT activities. GST activity remains stable or decreased slightly. In contrast to the littoral amphipods, the deep-layer inhabitant O. flavus showed no significant reaction to NOM exposure, probably due to decreased adaptive ability of this species. The stable environment of the Baikalean deep zones obviously does not provide triggers for the development of flexible antioxidant or general defense systems.