European sea bass is highly affected by outbreaks of viral nervous necrosis disease, provoked by the nervous necrosis virus (NNV). This virus displays a positive-sense RNA genome composed of two segments, RNA1, encoding the viral polymerase; and RNA2, encoding the capsid protein. Two genotypes of NNV have been detected in sea bass, although showing different virulence: RGNNV is highly virulent, whereas SJNNV replicates in sea bass brain without causing clinical signs. In the present work, the comparative analysis of the European sea bass immune response against both genotypes has been performed. The immune response has been evaluated in brain and head kidney of infected sea bass by relative real-time PCR of genes involved in the type I interferon system, and genes related to inflammatory and adaptive responses. In addition, a serological study, consisting of the ELISA quantification of IgM in sera, was also performed. The transcription analyses point out the importance of IFN system to control betanodavirus infections. The results obtained showed a strong induction of ifn-I, mxA, isg15 and isg12 in both organs analysed, especially in response to RGNNV. However, the response was quicker in head kidney of SJNNV inoculated sea bass, suggesting that this genotype induces a more rapid systemic response. Regarding the inflammatory response, RGNNV triggered a strong transcription of proinflammatory genes in brain, which provides evidences about the importance of the inflammatory process in NNV infection. Thus, the massive inflammatory process may be responsible for the eventual damage in nervous tissues, which would lead to fish dead. Finally, the high values of tr-g and mhc-b mRNA recorded in brain and the high IgM titer in sera, which was higher in SJNNV-inoculated fish, suggest that the adaptive response constitutes another important factor in the sea bass immune response against betanodaviruses, both at systemic and at local level.