Obesity in adults without Down syndrome is associated with an adverse metabolic profile including high prevalence of pre-diabetes and diabetes, high levels of insulin, non-high-density lipoprotein (HDL) cholesterol, leptin and high-sensitivity C-reactive protein (hsCRP) and low levels of HDL and adiponectin. We examined whether obesity in middle-aged adults with Down syndrome is also related to an adverse metabolic profile. This cross-sectional study included 143 adults with Down syndrome, with a mean age of 55.7±5.7years and 52.5% women. Body mass index (BMI) was classified as underweight (BMI<18.5kg/m2 ), normal (BMI 18.5-24.9kg/m2 ), overweight (BMI 25-29.9kg/m2 ) and obese (BMI≥30kg/m2 ). Diabetes was ascertained by history or by haemoglobin A1c (HbA1c) as normal glucose tolerance (HbA1c<5.7%), pre-diabetes (HbA1c 5.7-6.4%) and diabetes (HbA1c≥6.5%). We measured non-fasting lipids, hsCRP, insulin, adiponectin and leptin. The majority of the sample had an overweight (46.9%) or obesity (27.3%) status. However, there was a relatively low prevalence of pre-diabetes (9.8%) and diabetes (6.9%). Overweight and obesity status were not associated with lower HDL and adiponectin and higher insulin, non-HDL cholesterol and hsCRP as expected in adults without Down syndrome. However, overweight and obesity were strongly associated with higher leptin (P<0.001). The only metabolic correlate of obesity in middle-aged adults with Down syndrome was high leptin levels. Our findings are limited by non-fasting laboratory tests but suggest that middle-aged adults with Down syndrome do not have the adverse metabolic profile related to obesity found in adults without Down syndrome.