Background/Aims: Adipose tissue (AT) distribution is closely related to metabolic disease risk. Growth hormone (GH) reduces visceral and total body fat mass and induces whole-body insulin resistance. Our aim was to assess the effects of total and visceral AT (VAT) distribution and derived adipokines on systemic insulin resistance and lipid metabolism in acromegaly. Methods: Seventy adult patients with active acromegaly (43 males, age 49 ± 14 years) were evaluated before treatment, and a subset (n = 30, 20 males) was evaluated after treatment for acromegaly. Body composition and VAT, glucose metabolism parameters, lipids, C-reactive protein, and selected adipokines (vaspin, omentin, adiponectin, and leptin) were measured. Results: At baseline, VAT was positively associated with glucose metabolism parameters and with lipids. GH, but not IGF-I, was negatively associated with all AT depots (visceral, trunk, limbs, and total; 0.41 ≤ r ≤ 0.61, p < 0.001 for all) and positively associated with vaspin (r = 0.31, p = 0.013). The fat deposition after treatment was predominantly located on trunk and visceral depots. The lipid profile partially improved, with increases in HDL and apolipoprotein A-I and a decrease in lipoprotein(a). Vaspin decreased and omentin increased. Adiponectin and leptin did not change significantly. The improvement in homeostasis model assessment for insulin resistance (HOMA-IR) was best predicted by the decreases in IGF-I and vaspin and the lack of an increase in trunk fat (R2 = 0.59, p = 0.001). Conclusions: (1) VAT is a metabolic risk factor for patients with active acromegaly; (2) vaspin and omentin levels are influenced by the disease activity but are not associated with VAT mass; (3) fat deposition after treatment occurs predominantly on the trunk and in visceral depots, and (4) insulin resistance decreases and the lipid profile partially improves with treatment.