The aim of this study was to compare pathological lesions and viral antigen expression in the organs of mute swans (Cygnus olor) naturally infected with highly pathogenic avian influenza virus subtypes H5N1 and H5N8. The examination was conducted on the carcasses of 22 mute swans which died during the avian influenza outbreaks in Serbia in 2006 and 2016-2017. Avian influenza virus subtype H5N8 isolated from mute swans in 2016-2017 was clustered within the 2.3.4.4 clade group B. After necropsy, lung, liver, spleen, pancreas, kidney and brain tissues were sampled for histopathology and immunohistochemical examination. Avian influenza virus nucleoprotein polyclonal antibodies were used for detecting the viral antigen in the examined tissues. The most significant gross lesions were necrosis and haemorrhages in the pancreas. Major histological lesions were multifocal necroses in the pancreas, spleen and liver, non-purulent encephalitis, lung congestion and oedema. Immunohistochemical demonstration of HPAIV nucleoprotein in pancreas and brain was strongly consistent with histological lesions in both infected groups. Our findings showed that pancreas was the most affected organ in all examined mute swans. In addition to increased mortality rate, similar pathological findings were detected in mute swans naturally infected with highly pathogenic avian influenza viruses H5N1 and H5N8.