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Simple Summary: A tiny fraction of all introduced species worldwide successfully establishes viable populations that rapidly spread and negatively impact native biodiversity and ecosystem functioning—i.e., become invasive. Even so, invasive species exert adverse environmental, economic, and human health impacts globally. Thus, identification of successful invaders is one of the immediate challenges in invasion biology. Recent studies highlight species' immunity as an important component of invasion success since it enables invaders to adapt to the novel conditions as they expand their range. Here, we analyzed whether the immune response of the successful crayfish invader, the signal crayfish, changes as the invader encounters different environmental conditions and novel counterparts. We used several parameters, frequently applied to assess crayfish immunological status, and compared their cumulative pattern between sites along the signal crayfish invasion range in the Korana River, Croatia, as well as between the invasive signal crayfish and the native narrow-clawed crayfish. Immune response differed between native and invasive species and exhibited variations along the invasion range, which were mostly affected by water temperature and crayfish density. Our results indicate that changes in immunity may occur during range expansion, and imply that immunity could have a role in invasion success of invertebrate invaders. Immunity is an important component of invasion success since it enables invaders' adaptation to conditions of the novel environment as they expand their range. Immune response of invaders may vary along the invasion range due to encountered parasites/microbial communities, conditions of the local environment, and ecological processes that arise during the range expansion. Here, we analyzed changes in the immune response along the invasion range of one of the most successful aquatic invaders, the signal crayfish, in the recently invaded Korana River, Croatia. We used several standard immune parameters (encapsulation response, hemocyte count, phenoloxidaze activity, and total prophenoloxidaze) to: i) compare immune response of the signal crayfish along its invasion range, and between species (comparison with co-occurring native narrow-clawed crayfish), and ii) analyze effects of specific predictors (water temperature, crayfish abundance, and body condition) on crayfish immune response changes. Immune response displayed species-specificity, differed significantly along the signal crayfish invasion range, and was mostly affected by water temperature and population abundance. Specific immune parameters showed density-dependent variation corresponding to increased investment in them during range expansion. Obtained results offer baseline insights for elucidating the role of immunocompetence in the invasion success of an invertebrate freshwater invader. [ABSTRACT FROM AUTHOR]