We studied the immunological responses in the lung, brain and spleen of ducks and chickens within the first 7 days after infection with H7N1 highly pathogenic avian influenza (HPAI). Infection with HPAI caused significant morbidity and mortality in chickens, while in ducks the infection was asymptomatic. The HPAI viral mRNA load was higher in all investigated tissues of chickens compared with duck tissues. In the lung, brain and spleen of HPAI-infected chickens, a high, but delayed, pro-inflammatory response of IL-6 and IL-1β mRNA was induced, including up-regulation of IFN-β, IFN-γ, TLR3 and MDA-5 mRNA from 1 day post infection (p.i.). Whereas in ducks already at 8 h p.i., a quicker but lower response was found for IL-6, IL-1β and iNOS mRNA followed by a delayed activation of TLR7, RIG-I, MDA5 and IFN-γ mRNA response. Virus-infected areas in the lung of chickens co-localized with KUL-01+ (macrophages, dendritic cells), CD4+, and CD8α+ cells, during the first day after infection. However, only KUL-01+ cells co-localized with the virus after 1 day p.i. In ducks, CVI-ChNL-68.1+ (macrophage-like cells), CD4+ and CD8α+ cells and apoptosis co-localized with the virus within 8 h p.i. Apoptosis was detected in the brain and lung of HPAI-infected chickens after 2 days p.i. and apoptotic cells co-localized with virus-infected areas. In conclusion, excessive delayed cytokine inflammatory responses but inadequate cellular immune responses may contribute to pathogenesis in chickens, while ducks initiate a fast lower cytokine response followed by the activation of major pattern recognition receptors (TLR7, RIG-I, MDA5) and a persistent cellular response.