Rationale: In 2017, an American Thoracic Society/European Respiratory Society Task Force report recommended further research on the effects that body mass index (BMI) has on diffusing capacity of the lung for carbon monoxide (Dl_CO), the transfer coefficient (Kco), and the alveolar volume (VA). Objectives: Our goals were to 1) quantify the magnitude and direction of change to measured and predicted Dl_CO values as BMI increases in patients free of cardiopulmonary disease and 2) identify how BMI and obesity-related changes differ by reference set. Methods: Using data from a prospective cohort study of service members free of cardiopulmonary disease, we modeled the effect that BMI has on measured values of Dl_CO, Kco, and VA, after adjusting for age, sex, hemoglobin (Hgb), and height. We then referenced Dl_CO, Kco, and VA to normal values using four different reference equations. Results: There were 380 patients with data available for analysis, and 130 had a BMI ⩾ 30 kg/m² (87.7% class I obesity). After controlling for age, sex, Hgb, and height, increased BMI was significantly associated with Kco (β = 0.09, P < 0.01) and VA (β = -0.15, P < 0.01) but not Dl_CO. After adjustment for Hgb, for every 5-kg/m² increase in BMI, the mean increase in percent predicted (PPD) values ranged from 4.2% to 6.5% and from 5.0% to 7.5% for Dl_CO and Kco, respectively; and the mean decrease in VA PPD was 3.2-4.0%. In the presence of obesity (BMI ⩾ 30 kg/m²), the prevalence of Dl_CO and Kco abnormalities dropped by 4.1-12.1% and 0.4-16.3%, respectively, across equations, whereas VA abnormalities increased from 7.7% to 9.9%. Eliminating 163 patients with abnormal trans-thoracic echocardiogram (TEE), high-resolution computed tomographic (HRCT) scan, or Hgb altered the magnitude of relationships, but significance was preserved. Conclusions: In an otherwise healthy population with predominantly class I obesity and normal TTE, HRCT scan, and Hgb, we found that Kco and VA were more affected by BMI than Dl_CO. Increases in PPD values varied across equations and were modest but significant and could change clinical decision making by reducing sensitivity for detecting gas-exchange abnormalities. BMI and obesity had the smallest effect on Global Lung Function Initiative PPD values.

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