Hyperpolarized 3 He (HP 3 He) MRI shows promise to assess structural and functional pulmonary parameters in a sensitive, regional, and noninvasive way. Structural HP 3 He MRI has applied the apparent diffusion coefficient (ADC) for the detection of disease-induced lung microstructure changes at the alveolar level, and HP 3 He pulmonary partial pressure of oxygen (pO 2 ) imaging measures the oxygen transfer efficiency between the lung and blood stream. Although both parameters are affected in chronic obstructive pulmonary disease (COPD), a quantitative assessment of the regional correlation of the two parameters has not been reported in the literature. In this work, a single acquisition technique for the simultaneous measurement of ADC and pO 2 is presented. This technique is based on the multiple regression method, in which a general linear estimator is used to retrieve the values of ADC and pO 2 from a series of measurements. The measurement uncertainties are also analytically derived and used to find an optimal measurement scheme. The technique was first tested on a phantom model, and then on an in vivo normal pig experiment. A case study was performed on a COPD patient, which showed that in a region of interest ADC was 29% higher while oxygen depletion rate was 61% lower than the corresponding global average values. Magn Reson Med 61:1015-1021, 2009.