Background: In health volunteers, the single-breath diffusing capacity of the lung for carbon monoxide (D-LCO) decreases and D-LCO normalized per liter alveolar volume (V-A; D-LCO/V-A) increases if V-A is decreased. We hypothesized that comparison of D-LCO/V-A with its predicted value at predicted total lung capacity (TLC) will result in an underestimation of the diffusion disorder in patients with a restrictive lung disease, if a similar relationship exists between D-LCO/V-A and lung volume as found in healthy volunteers. Objective: To test this hypothesis, we studied total gas transfer D-LCO and D-LCO/V-A as functions of V-A in patients who developed a restrictive lung disease and a diffusion disorder in a short period of time. Design: An observational survey. Setting: Pulmonary function department. Patients: Thirteen patients without any initial pulmonary pathology who developed the mentioned pulmonary pathology due to bleomycin treatment. Interventions: Bleomycin treatment. Measurements and results: We performed the single-breath test at various V-A levels before, during, and after bleomycin treatment. In the majority of the patients, the D-LCO vs V-A relationship remained parabolic, but shifted downwards during therapy. Therefore, the linear D-LCO/V-A vs V-A relationship shifted downwards, while the negative slope was not changed, indicating the development of a decreased gas transfer. Six patients also developed a volume restriction. Conclusions: The agreement of the data with the hypothesis increased its probability. Consequently, to evaluate a diffusion disorder, D-LCO/V-A at a lower actual TLC of patients with a lung restriction should be compared to a reference D-LCO/V-A at a lung volume equal to the actual TLC.