Antimalarial drugs are used for the control of mild manifestations of autoimmune diseases due to their low toxicity. Hydroxychloroquine (HCQ), a alpha-hydroxylated derivative of chloroquine, is usually preferred because of its higher tolerability. Mild and unspecific gastrointestinal symptoms are the main secondary effects related to HCQ use. Less than 1% of subjects show liver enzyme increase, although the percentage can be as high as 50% in subjects with chronic liver disease. A woman with mixed connective tissue disease who developed a reversible acute hepatitis shortly after the initiation of low-dose HCQ is presented. Two previous cases of patients with acute liver failure have previously been published. All three cases have been reported in the absence of previous liver disease. It seems to be a dose-dependent, idiosyncratic, and molecule-specific toxic effect and must be considered, taking into account the potential bad prognosis.