Vinasse is one of the major sources of environmental pollution because of high organic matter and toxic compound levels (e.g., sulfates and phenols). The more the vinasse treatment is, the less the environmental pollution will be. This study aimed to evaluate the effect of a low-cost and simple anaerobic pretreatment on the COD removal efficiency of the UASB reactor for the treatment of synthetic vinasse. In addition, this system was evaluated through organic loading rate (OLR), hydraulic retention time (HRT), upflow velocity (Vup), mixed liquor volatile suspended solid (MLVSS), mixed liquor suspended solids (MLSS), and pH. In a 155-day trial, the system was fed by synthetic vinasse with an organic loading rate (OLR) ranging from 2.5 to 20.5 kgCOD/m3.d. The results indicated that when a UASB reactor was used for synthetic vinasse treatment, the average COD removal efficiency and methane production were about 80.45% and 56%, respectively. However, the use of an anaerobic unit as a less expensive and simple pretreatment increased COD removal efficiency to 88.4% and methane production to 62.5% (684.6 L/kgCOD). The study result suggested that anaerobic pretreatment is suitable for reducing the environmental pollution of vinasse and can be used as an economical system for real vinasse treatment on an industrial scale.