The relative responses of the Wintrobe and the Westergren erythrocyte sedimentation rate methods to increasing plasma concentrations of asymmetric macromolecules were investigated. The study was aided by the use of a recently described ESR method, the Zeta Sedimentation Ratio (ZSR). The ZSR, like the Wintrobe and Westergren methods, responds to an increase in the plasma content of asymmetric macromolecules which commonly accompanies inflammatory disease. Unlike these two methods, the ZSR is insensitive to hematocrit variation. At present, ESR results are usually corrected for hematocrit effects by the exercise of clinical judgment. Even under favorable circumstances this approach appears to be the least effective of all the approaches investigated. Contrary to the prevailing opinion, the Westergren method is less sensitive than the Wintrobe method to minimal elevations of asymmetric macromolecules. It is nonlinear in its response at these low levels. In contrast, the rapid onset of the packing phase renders the Wintrobe method insensitive to marked elevations of asymmetric macromolecules, a region where the Westergren method performs extremely well.