Sea hares, Aplysia dactylomela, are soft bodied Opisthobranch mollusks which inhabit the shallow water of the Red sea. They release purple and sticky ink secretion towards the attacker to defend themselves. Sea hares caused many cases of human toxicity especially in people of some Asian countries who used to feed on it as in Japan, China, Philippines and Fiji. The present study was undertaken to extend our investigation of the effect of sea hares ink on mammalian cells especially the splenic macrophages and make an alarm for people who feed on sea hares. Forty male albino mice were divided into 4 groups; control group and three treated groups were injected intraperitonealy with a sublethal dose of the ink. The treated mice were dissected after 1, 7, and 30 days. Spleen tissue samples were examined histologically and immunohistochemically using pan macrophage marker CD68. After one day, large macrophages were observed with large nuclei and irregular clumps of chromatin. Many lysosomes were detected. After 7 days, there was a significant increase in the number of positive macrophages with enlarged size. They had lobulated euchromatic nuclei with peripheral heterochromatin. The cytoplasm was crowded and had swollen mitochondria with destructed cristae. After 30 days, macrophages were shrunk, deeply stained and many apoptotic bodies were detected. The results showed characteristic apoptotic splenic macrophages induced by the ink fluid of A. dactylomela.