Potential crop yield loss due to early-season weed competition is an important risk associated with postemergence weed management programs. WeedSOFT is a weed management decision support system that has the potential to greatly reduce such risk. Previous research has shown that weed emergence time can greatly affect the accuracy of corn yield loss predictions by WeedSOFT, but our understanding of its predictive accuracy for soybean yield loss as affected by weed emergence time is limited. We conducted experiments at several sites across the Midwestern United States to assess accuracy of WeedSOFT predictions of soybean yield loss associated with mixed-species weed communities established at emergence (VE), cotyledon (VC), first-node (V1), or third-node (V3) soybean. Weed communities across research sites consisted mostly of annual grass species and moderately competitive annual broadleaf species. Soybean yield loss occurred in seven of nine site-years for weed communities established at VE soybean, four site-years for weed communities established at VC soybean, and one site-year for weed communities established at V1 soybean. No soybean yield loss was associated with weed communities established at the V3 stage. Nonlinear regression analyses of predicted and observed soybean yield data pooled over site-years showed that predicted yields were less than observed yields at all soybean growth stages, indicating overestimation of soybean yield loss. Pearson correlation analyses indicated that yield loss functions overestimated the competitive ability of high densities of giant and yellow foxtail with soybean, indicating that adjustments to competitive index values or yield loss function parameters for these species may improve soybean yield loss prediction accuracy and increase the usefulness of WeedSOFT as a weed management decision support system.