High-solids mesophilic anaerobic digestion (HS-MAD) processes employing thermal hydrolytic pretreatment (THP) have gained much interest in recent years; primarily because they have been shown to produce Class A biosolids in accordance with EPA 503 regulations, but also because they represent an economical approach to the maximization of available anaerobic digester volume. The wide-scale application of this technology is limited by concerns of operational stability, ammonia toxicity, and the plant-wide impacts of the concentrated return flows from downstream dewatering processes. HS-MAD is operated at double the solids concentration of a mesophilic anaerobic digester (MAD). Furthermore, this study shows that HS-MAD can be successfully applied to treat thickened wastewater sludge that has undergone THP, achieving similar rates of volatile solids and COD reduction as well as methane production as a conventional mesophilic anaerobic digestion process (MAD) at a 25% shorter solids retention time. The overall volume required for HS_MAD is thus between 30-40% of volume required for MAD (taking thickening and lower process SRT into account). HS-MAD was operated at ammonia concentrations up to 2900 mg/L NH3-N with no apparent inhibition of methanogenesis. Dewatering process return streams from HS-MAD did indeed have higher concentrations of ammonia and organic nitrogen than the conventional process, but at a volume of less than half of what would result from low-solids conventional MAD. Post treatment of digested sludge, enhanced dewatering with inorganic coagulants, and variations to the hydrolysis reactor’s operation hold promise for improving the quality of these streams. The impact of these return stream constituents on the overall nitrogen balance of the treatment plant would need to be balanced against the potential benefits of THP in terms of higher solids loading and a smaller reactor size.