The accumulation of volatile fatty acids during the anaerobic digestion of biodegradable substrate such as Source Sorted Organic Fraction of Municipal Solid Waste (SS-OFMSW) is associated with an inhibitory effect on methane producing biochemical pathways. While inconclusive at times, the usage of two-stage digesters has been argued as a potential solution for this issue. In this study single-stage vs. two-stage thermophilic digesters, fed with SS-OFMSW, were examined during the startup phase while increasing the loading rate from 0.5 to ~2 g VS.L-1d-1. While both systems exhibited a stable performance, with neutral pH and low intermediate-to-partial alkalinity, the two-stage digester exhibited better effluent quality with 79 and 57% lower average total 16 chemical oxygen demand (TCOD) and soluble COD (SCOD), respectively. Also, upon reaching steady-state conditions, the two-stage system showed a superior performance with an overall methane content of 54%, compared to an average of 45% in the single-stage system.