Objective Mitotane is used in the treatment of adrenocortical carcinoma (ACC). Metabolic and hormonal side effects of mitotane, the effect of subsequent treatment with statins and hormones and the effects of discontinuation of mitotane were assessed. Patients and methods Fifty patients were included. Lipid profiles, thyroid hormones, sex hormones and adrenal function from first year of mitotane treatment and after cessation were evaluated. Results After 6 months of mitotane treatment total cholesterol increased from (median) 5.1 (IQR 4.3 to 5.8) to 7.4 (6.2–9.0) mmol/L, p < .001. LDL, HDL and triglyceride also increased, all p ≤ .03. Three months of treatment with statins decreased total and LDL-cholesterol, and cessation of mitotane led to further reduction in lipids. Plasma thyroxine decreased from 90 (78–111) to 57 (47–63) nmol/L and free thyroxine from 16.0 (13.0–18.3) to 11.7 (10.5–12.6) pmol/L on mitotane, both p < .001, while TSH remained unchanged. Treatment with thyroxin significantly increased plasma thyroxine and free thyroxine and decreased TSH. Cessation of mitotane increased total T4 (p < .001). Mitotane increased plasma SHBG from 36 (22–51) to 189 (85–259) nmol/L and LH from 4.6 (1.6–8.1) to 20.0 (10.0–34.9) IU/L, both p < .001. In males the changes were accompanied by an increase in testosterone from 9.8 (7.2–14.5) to 27.0 (15.3–34.8) nmol/L, p < .03. Fifteen of 24 tested patients regained normal adrenal function 6 (3–16) months after cessation of mitotane. Conclusions Mitotane treatment exerts multiple severe side effects involving both the metabolic and endocrine systems that may require treatment, but the effect appears to be partially reversible.