Abstract Background Inflammation is associated with increased resting energy expenditure (REE) in patients with chronic kidney disease. Oxidative stress, on the other hand, appears not to increase REE. Smoking is a common mechanism for generating oxidative stress and inflammation. Whether smokers have increased REE and if so, whether it is accounted for by the pro-oxidant and inflammatory state is not known. Methods A case control study of 11 smokers and 24 non-smokers with overt diabetic nephropathy was performed to evaluate the chronic effect of smoking on REE. REE (indirect calorimetry), glomerular filtration rate (iothalamate clearance), markers of oxidative stress (urinary and plasma malondialdehyde (MDA), and protein carbonyls) and inflammation (C-reactive protein, tumor necrosis factor-alpha, interleukin-6) were measured on two occasions four months apart. Results Biomarkers of inflammation (C-reactive protein) and oxidative stress (urinary and plasma MDA) were increased in smokers. REE was increased in smokers, 24.3 kcal/kg/day compared to 21 kcal/kg/day (p = 0.009) in non-smokers. After adjusting for age, GFR, MDA, C-reactive protein, and hemoglobin A₁C the difference in REE between the two groups persisted (adjusted difference 3.51 kcal/kg/d, 95% confidence interval 0.59 – 6.45, p = 0.020). Conclusion Patients with overt diabetic nephropathy who smoke have a higher REE, oxidative and inflammatory state. Elevated REE is not attributable to heightened oxidative stress and inflammatory state. Smoking is an independent risk factor for elevated REE in patients with diabetic nephropathy and provides an additional mechanism by which it may lead to poor outcomes.