The principal idea of this paper is to simulate and evaluate the determination of first-order degradation rate constants at heterogeneous contaminated sites under realistic conditions. First, a set of heterogeneous and contaminated synthetic aquifers is generated; second, the spreading of a solute plume subject to first-order degradation is simulated. Third, this plume is investigated using "monitoring wells" placed along the presumed plume center line. Using only piezometric heads, concentrations and hydraulic conductivities obtained at these monitoring wells, first-order degradation rate constants are calculated by methods typically used in field applications. The estimated rate constants are compared to the "real" value known from the simulations. This comparison is conducted for different degrees of heterogeneity, represented by lognormally distributed random conductivity fields. The results indicate that, with increasing degree of heterogeneity, "measured" degradation rate constants become uncertain with a high variability around the true constant. Measured rate constants tend to overestimate the true constant by up to one order of magnitude. A sensitivity analysis of the influences of source width, transport velocity, and dispersivity shows that (1) with increasing source width, measured rate constants decrease their relative error and increase their accuracy; (2) the choice of dispersivity can produce both over- and under-estimation of the true rate constant; and (3) that large-scale measurements of hydraulic conductivity yield better estimates of flow velocities as compared to local scale measurements. These results explain in part the high variability of field measured degradation rate constants reported in the literature.