A variable-gain controller for anaerobic digestion of industrial winery wastewater is presented. A control law using both volatile fatty acids (VFA) and methane production rate as controlled variables and organic loading rate (OLR) as manipulated variable is defined. The process state is quantitatively estimated by an empirical function comparing VFA measurements against a setpoint value; then, it is modified with a second empirical function that compares the methane flow rate with a maximum capacity reference, and finally it is adjusted with a third factor considering the actual hydraulic retention time. The variable-gain function determines the extent of the OLR change applied to the system. The controller was successfully validated in a 95 L upflow-anaerobic-sludge-blanket (UASB) reactor, treating industrial wine wastewater at OLR ranged between 2.0 and 39.2 g COD/L d for 120 days at mesophilic conditions. Higher performance was achieved contrasted with a conventional strategy carried out in a parallel UASB unit.