To study the epidemiology and evolution of norovirus (NoV) in immunocompromised patients in a tertiary hospital in China. Stool specimens were collected from 131 hospitalized patients presenting with diarrhea from July 1, 2012, to June 30, 2013, and were tested for NoV using RT-PCR. RT-PCR was performed to amplify the complete capsid genome for a series of samples from chronic diarrhea patients, and nucleotide and amino acid changes were analyzed. There were nine NoV-positive patients among 124 immunocompromised patients (7.3%); all nine were infected with GII.4 Sydney_2012 strain. In three chronic diarrhea patients, the GII.4 Sydney_2012 strains accumulated 19, 18, and eight nucleotide mutations within 110, 113, and 22 days, respectively, most were non-synonymous. The greatest number of stable amino acid mutations was 10 in patient 2; eight stable mutations (including three in antigenic sites) occurred while the patient was asymptomatic and shedding the virus. GII.4 Sydney_2012 strain tends to undergo stable mutations during the asymptomatic shedding phase and may generate new variants in chronic diarrhea patients. J. Med. Virol. 88:224–233, 2016. © 2015 Wiley Periodicals, Inc.