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.