The role of diffusion-weighted magnetic resonance imaging (DWI) to differentiate breast lesions in vivo was evaluated. Sixty women (mean age, 53 years) with 81 breast lesions were enrolled. A coronal echo planar imaging (EPI) sequence sensitised to diffusion (b value=1,000 s/mm(2)) was added to standard MR. The mean diffusivity (MD) was calculated. Differences in MD among cysts, benign lesions and malignant lesions were evaluated, and the sensitivity and specificity of DWI to diagnose malignant and benign lesions were calculated. The diagnosis was 18 cysts, 21 benign and 42 malignant nodules. MD values (mean +/- SD x 10(-3) mm(2)/s) were (1.48 +/- 0.37) for benign lesions, (0.95 +/- 0.18) for malignant lesions and (2.25 +/- 0.26) for cysts. Different MD values characterized different malignant breast lesion types. A MD threshold value of 1.1 x 10(-3) mm(2)/s discriminated malignant breast lesions from benign lesions with a specificity of 81% and sensitivity of 80%. Choosing a cut-off of 1.31 x 10(-3) mm(2)/s (MD of malignant lesions -2 SD), the specificity would be 67% with a sensitivity of 100%. Thus, MD values, related to tumor cellularity, provide reliable information to differentiate malignant breast lesions from benign ones. Quantitative DWI is not time-consuming and can be easily inserted into standard clinical breast MR imaging protocols.