BACKGROUND Cheese whey is a byproduct of the dairy industry, which is characterized by its high organic matter content, so its valorization by anaerobic digestion (AD) requires a pretreatment or a dilution that allows high values of degradability. However, this increases the cost and duration of whey treatment. In this paper, a study on the viability of anaerobic treatment of a type of crude whey is presented. For it, the effect of pH, substrate–inoculum ratio (S:I) and its interaction during mesophilic AD of raw cheese whey were evaluated. The interactions of the parameters were analyzed by response surface analysis. RESULTS The results showed that in the mesophilic temperature range, the pH most suitable for AD of whey is slightly alkaline (pH = 8). Production and methane yield were improved, increasing the proportion of raw whey, which means that it is possible to operate with high organic loading rate, maintaining adequate operation conditions (pH = 8, T = 40 °C). The best performance of the digester reached 7.1 LCH4 Lwhey−1, and a specific methanogenic activity of 1.15 gCOD gTVSi−1 day−1. CONCLUSION It is possible to use raw cheese whey to produce methane. The alkaline pH and high S:I ratio improved the methane yield and promote methanogenic activity. Intermediate compounds (volatile fatty acids, NH3 and/or H2S) accumulated during the AD operation, which could have influenced the reactor performance; hence, further study is advisable to elucidate their effect on the global process. © 2020 Society of Chemical Industry