Hepatitis B virus infection is still a major global health problem, despite decades of research. Interleukin (IL)-22 induces acute phase reactants and chemokines, favors anti-microbial defence and protects tissues from damage. IL-22 is important in chronic skin inflammation, but its role in chronic hepatitis B (CHB) is unclear. This study explores the association between intra-hepatic IL-22 expression, its relevant associated cytokines and the severity of liver inflammation/fibrosis in CHB patients. IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines (CXCL-9, CXCL-10, CXCL-11), fibroblast growth factors and Kupffer cell (KC) numbers were measured in patients with CHB (n=65), acute hepatitis B (AHB; n=4), chronic hepatitis C (CHC; n=14) and non-viral hepatitis (n=23), using immunohistochemistry. Expression of IL-22, IL-17, IL-10, IL-6, non-ELR-CXC chemokines and number of KCs in liver tissues were substantially higher in AHB patients than others. In CHB patients, the expression of IL-22, IL-6, CXCL-9 and CXCL-10 were significantly higher with alanine aminotransferase (ALT) levels ≤ twice the upper limit of normal (ULN), compared with those with ALT levels >twice the ULN, whereas IL-10 and IL-17 showed a reverse pattern. IL-22 was inversely (P<0.01), but IL-17 was positively (P<0.05), correlated with the histological activity index) in these patients, and a significant negative correlation between the fibrosis stage and IL-22 or non-ELR-CXC chemokines was observed. Furthermore, immunofluorescent labeling demonstrated a close spatial association of IL-22, CXCL-9, -10 or -11 in the CHB liver. We speculate that IL-22 and non-ELR-CXC chemokines synergistically may provide protection in liver inflammation/fibrosis during CHB infection.