Summary Context Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. Objective To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above‐mentioned variables between patients with active acromegaly and controls. Design and setting This open cross‐sectional study was conducted at a University Hospital. Patients Twenty‐two outpatients were compared with sex‐ and age‐matched control subjects. Main outcomes Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. Results Patients presented higher triglyceride (median IQR) (1·21·1–1·6 vs 0·90·6–1·1 mm, P < 0·05), low‐density lipoprotein‐cholesterol (LDL‐C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized‐LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin‐1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·250·1–0·9 vs 0·850·4–1·4 mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM‐1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high‐density lipoprotein‐cholesterol (HDL‐C) (30%) and CETP activity (28%), while GH independently predicted LDL‐C (18%), oxidized‐LDL (40%) and endothelin‐1 levels (19%). Conclusions In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro‐oxidative and pro‐inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL‐C, ox‐LDL and endothelin‐1.