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An outbreak of hydropericardium syndrome has been ongoing in East China since 2015. To decipher the disease etiology, 26 full-length sequences of the adenovirus hexon gene were cloned and sequenced. Phylogenetic trees and sequence alignments revealed that all 26 strains belonged to subgroup C serotype 4 and shared some consistent molecular characteristics that showed only 9 mutations without amino acid (AA) deletions. Eight sites were located in L1 and one in L2. To determine whether the complete hexon gene was under positive selection pressure, site-by-site analysis was performed to identify specific codons that underwent evolutionary selection. Analysis identified 7 positively selected codons in L1 (AA 164, 168, 195, and 243) and L2 (AA 379, 402, and 408). The other 2 sites (AA 140 and 680) were located in P1 and P2, respectively. The results reveal that hexon loops L1 and L2 are hypervariable regions. Moreover, elucidation of viral distribution indicated that the liver is a major target organ, and FAdV-4 is a pantropic virus. In summary, FAdV-4 has been identified as an epidemic strain, and viral evolution is ongoing; thus, continuous surveillance of this virus will contribute to the control of future epidemics.