Thousands of high production volume (HPV) chemicals are used in the US at rates exceeding 450000 kg (1 million pounds) per year, yet little is known about their fates during wastewater treatment and upon release into the environment. We utilized a recently introduced empirical model to predict the fraction of the mass loading (in raw sewage) that is expected to persist in digested sludge following conventional municipal treatment of chemical-laden sewage. The model requires only two readily available input parameters, a compound's log KOW value and a dimensionless curve fitting parameter (pfit). Following refinement of the fitting parameter and cross-validation of the model using the Jackknife method, we predicted the mass fractions of 207 hydrophobic HPV chemicals (log KOW of ≥4.0) that are expected to accumulate in digested municipal sludge during conventional wastewater treatment. Using this screening approach in conjunction with information from toxicity databases, we identified 11 HPV chemicals that are of potential concern due to (i) their propensity to accumulate and persist in sludge (>50% of mass loading), (ii) unfavorable ecotoxicity threshold values, and (iii) structural characteristics suggestive of environmental persistence following release of these HPV chemicals on land during biosolids recycling. The in silico screening approach taken in this study highlights existing environmental monitoring needs and may guide risk management strategies for biosolids disposal.