Controlled trials have suggested that opiate antagonist therapy may be effective for the treatment of the symptoms of cholestasis. The oral opiate antagonist naltrexone in particular has started to enter into routine clinical use for amelioration of cholestatic itch. Attention regarding the side effects of opiate antagonist therapy has, to date, largely focused on an opiate withdrawal-type reaction (which can be controlled effectively by titrated therapy introduction regimens). Here we describe 3 cases of a further clinically important side effect, loss of control of pain resulting from other pathologies, which in each case necessitated the withdrawal of hitherto clinically effective opiate antagonist therapy. Of the 14 patients treated by our unit with opiate antagonist agents for the control of cholestatic symptoms, 13 (93%) showed resolution of, or significant improvement in, symptoms. Of the 13 patients showing a clinical response, 7 (54%) subsequently had to discontinue therapy because of side effects (including the 3 patients with uncontrolled pain). It is our experience that in the routine clinical setting, opiate antagonists are highly effective for the treatment of cholestatic symptoms. In practice, however, their usefulness is limited by their side-effect profile.