The immunotoxic effects of cadmium (Cd) exposure in bivalves are poorly understood and whether or not stimulation of the immune system exacerbates Cd toxicity is unclear. The mussel Mytilus edulis was exposed to 20 or 50 μg/l total Cd for up to 11 days compared to no added Cd controls to assess immune and other physiological responses. Selected experiments were then repeated in the presence of a lipopolysaccharide (LPS) challenge with and without subsequent Cd exposure. Immune functions of hemocytes, hematology, hemolymph glucose and ion content, as well as superoxide dismutase (SOD) activity and organ pathology were measured. Cd accumulated mainly in digestive gland and gills and to a lesser extent in the adductor muscle. Exposure to 20 μg/l Cd alone caused a transient modulated of phagocytosis and increased neutral red retention (Kruskal-Wallis, p = 0.002). The higher Cd concentration also increased cytotoxicity, and decreased hemocyte count. Changes in hemolymph Na(+), K(+), and glucose were small or negligible. Histopathological examination showed tissue injuries consistent with inflammation and necrosis in the gills, digestive gland, and adductor muscle during Cd exposure alone. LPS injection alone and LPS + Cd caused an increase in the number of circulating hemocytes by the end of the experiment (Kruskal-Wallis, p = 0.01) and a transient rise in phagocytosis at day 4 (analysis of variance (ANOVA), p = 0.001). The LPS + Cd treatment also caused transient changes in neutral red retention and in the cytotoxicity of hemocytes compared to controls. Intracellular SOD activity did not change in hemocytes under any treatment. Tissue inflammation and pathology was greatly increased by the effect of Cd exposure with an LPS injection compared to either treatment alone. We conclude that immunostimulation with LPS can greatly increase Cd-related organ pathologies but does not necessarily alter the responses of hemocytes.