Background: β-Glucosylceramide, a naturally occurring glycolipid, exerts modulatory effects on natural killer T (NKT) lymphocytes. Aim: To determine whether β-glucosylceramide can alter NKT function in opposite directions, colitis was induced by intracolonic installation of trinitrobenzenesulphonic acid, and hepatocellular carcinoma (HCC) was induced by transplantation of Hep3B cells. Methods: The immunological effect of β-glucosylceramide was assessed by analysis of intrahepatic and intrasplenic lymphocyte populations, serum cytokines and STAT protein expression. Results: Administration of β-glucosylceramide led to alleviation of colitis and to suppression of HCC, manifested by improved survival and decreased rumour volume. The beneficial effects were associated with an opposite immunological effect in the two models: the peripheral:intrahepatic CD4:CD8 lymphocyte ratio increased in the colitis model and decreased in the HCC group. The peripheral:intrahepatic NKT lymphocyte ratio decreased in β-glucosylceramide-treated mice solely in the HCC model. The effect of β-glucosylceramide was associated with decreased STAT1 and 4 expression, and with overexpression of STAT6, along with decreased interferon γ levels in the colitis model, whereas an opposite effect was noted in the HCC model. Conclusions: β-glucosylceramide alleviates immunologically incongruous disorders and may be associated with "fine tuning" of immune responses, by changes in plasticity of NKT lymphocytes.