The extensive use of foliar-applied protoporphyrinogen oxidase (PPO)-inhibiting herbicides indisputably contributes to the continued selection of waterhemp resistant to PPO-inhibiting herbicides (PPO-R). However, the role of soil-residual applications of PPO-inhibiting herbicides in the selection of PPO-R has been clouded by the efficacy that these herbicides have on PPO-R waterhemp. The aim of the present study was to understand if soil-residual PPO-inhibiting herbicides have the potential to influence the proportion of resistant waterhemp in emerging plants as herbicide concentrations diminish in the soil. Greenhouse and field experiments were conducted in a PRE dose-response experiment testing fomesafen or fomesafen plus s-metolachlor in the presence of mixed seed populations of PPO-R and -susceptible (S) waterhemp. The first 20 (greenhouse) or 10 (field) waterhemp plants that survived the residual herbicide treatment were sampled for genotypic analysis to detect the presence of the allele responsible for PPO-R in waterhemp (ΔG210). Relative to the nontreated control, the highest rate of fomesafen increased the frequency of resistance (FOR) by 70% in the greenhouse experiments and 20% in the field experiments. The addition of s-metolachlor did not reduce the fomesafen-induced increase in the FOR in the surviving plants from field or greenhouse experiments. However, the additional herbicide from an alternate site of action (s-metolachlor) substantially improved soil-residual herbicide efficacy over fomesafen alone, which limited the number of waterhemp plants surviving the herbicide application. Thus, the selection for resistance can be delayed with the addition of a herbicide from an alternative site of action by postponing and/or reducing waterhemp emergence. These data strongly suggest that soil-residual PPO-inhibiting herbicides can influence the FOR in a field population, placing even greater importance on the implementation of best management practices such as full herbicide use rates and using herbicides from multiple sites of action to mitigate the risk of selecting for herbicide-resistant weed biotypes.