The myxosporean parasite Enteromyxum leei invades the intestine of gilthead sea bream producing a slow-progressing disease, which may end in the death of fish. The present work aimed to better know the host immune response and the underlying molecular mechanisms, which may help to understand why some individuals seem to be refractory to the disease. Three main aspects involved in fish health and welfare (immune, growth and redox status) were studied in fish exposed to E. leei-contaminated effluent, in comparison with control animals (not exposed to the disease). After chronic exposure (113days), prevalence of infection was 67.8%. Among exposed fish, parasitized and non-parasitized fish exhibited clear differences in some of the measured innate immune factors (respiratory burst, serum peroxidases, lysozyme and complement), and in the expression of immune, antioxidant and GH-related genes. The respiratory burst of parasitized fish was significantly higher, and serum peroxidases and lysozyme were significantly decreased both in parasitized and non-parasitized fish. The gene expression of GHR-I, GHR-II, IGF-I and IGF-II was measured in head kidney (HK) samples, and that of interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, alpha-2M, GR, GPx-1 and GRP-75 was measured in intestine and HK samples, by rtqPCR. Parasitized fish exhibited a down-regulation of IL-1beta, TNF-alpha and GPx-1 in the intestine, and GHR-I and IGF-I were also down regulated in HK. alpha-2M and GRP-75 were over-expressed in the intestine of parasitized animals. Non-parasitized fish had increased transcripts of GHR-I and IGF-I with respect to control animals, which could furnish their immunocytes with an advantage to combat the parasite. The expression of GHR-II and IGF-II was not altered by the parasite challenge.