The calculation of polar surface areas (PSA) from the electron density using quantum chemical topology (QCT) and a newly developed algorithm to determine isodensity surface areas is described. PSA values were calculated from the atomic partitioning of B3LYP/6-311G* wavefunctions and the results described herein represent the first application of this new algorithm. PSA values were calculated for forty drugs and compared to the topological polar surface area (TPSA) and those calculated by the QikProp program. Oral bioavailabilities predicted from the QCT PSA values for a subset of twenty drugs (the Palm set) were similar to those predicted by the dynamic polar surface area (DPSA) and in general, are in agreement with the observed values. Overall, PSA values obtained from QCT were generally similar to the DPSA, TPSA, and QikProp values, though differences in fragment contributions were found, with nitrogen-bearing functional groups showing the largest variation between methods. Differences between methods showed how the calculation of the PSA is dependent on the method used and, therefore, judicious application of the upper limits used in the prediction of oral bioavailability is warranted. These results also indicate that, because of the differences in the way PSA values are calculated, values from the different methods should not be used interchangeably.