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We evaluated the relative accuracy of calculating apparent diffusion coefficients (ADCs) of intracranial tissues using a two-point versus a six-point regression technique. Echo planar diffusion-weighted MRI was performed at 1.5 T in three standard locations and in pathologic regions in 10 subjects using gradient strengths corresponding to b values of 1, 100, 200, 500, 800, and 1,000 s/mm2. Estimation of ADCs was made using two methods: a nonlinear regression model using measurements from the full set of b values (six-point technique) and linear estimation using b values of 1 and 1,000 only (two-point technique). A high correlation between the two methods was noted (R2 = 0.999), and the mean percentage difference was 0.84%. These results suggest there is little error in estimating brain ADCs using a two-point technique.