Very small amounts of impervious cover can impact streamflows. In the Potomac basin, for example, significant streamflow alteration associated with watershed impervious cover >0.5%–2.0% have been found. Since these impacts were found with considerably lower amounts of impervious cover than previously documented in the literature, typically 10%–20%, this study evaluated whether certain watershed characteristics (e.g., watershed area, karst geology, precipitation, soil characteristics, physiographic province, and slope) make a stream reach more susceptible to the impacts of impervious cover than others. The results of this study indicate there are differences in streamflow sensitivity to impervious cover given certain landscape characteristics. The relationships of watershed characteristics with streamflow alteration in flashiness, high flow duration, and low pulse duration were evaluated. Flashiness alteration was positively correlated with impervious cover and influenced by watershed slope and area. High flow duration alteration was negatively correlated with impervious cover and influenced by mean annual precipitation and slope. Low pulse duration was poorly correlated with the watershed characteristics under consideration. These differences may assist in land management efforts and heighten awareness of the environmental impacts of impervious cover.