In this work phase equilibrium conditions for structure II (sII) gas hydrates in systems containing a mixture of salts (NaCl, KCl, CaCl2, MgCl2) and methanol have been measured using a high-pressure cell. The concentration of salts in aqueous solution (model of reservoir water) was constant in all experiments and equal to 18 wt%. Phase equilibrium conditions were determined by the isochoric method for pressures ranging from 1 to 4.7 MPa and for mass fraction of methanol from 0 to 50 wt%. The experimental data were obtained for water + salts, water + methanol, and water + salts + methanol systems. From the results obtained, it follows that 20 wt% of methanol in distilled water (DW) gives the thermodynamic shift of the hydrate decomposition temperature close to the brine one. Mixtures of 10% methanol + brine and 20% methanol + brine significantly better reduce the equilibrium temperature of hydrate dissociation compared to samples with the similar total mass fraction of inhibitor (methanol) in water (30, 40 wt%). At the pressures of more than 4 MPa combination of 20 wt% methanol + brine provide the same thermodynamic inhibition as 50 wt% of methanol in water. Thus, the synergism of the methanol + salts mixtures in the thermodynamic inhibition of sII gas hydrates has been observed. Synergism manifested itself in a greater shift of equilibrium curves to lower temperatures and higher pressures compared to systems containing only one thermodynamic hydrate inhibitor (THI). The obtained results indicate the possibility of a significant reduction in the consumption of polar organic THI for gas hydrate prevention in deposits with highly mineralized brine. However, it is necessary to take into account the possible complications associated with the precipitation of salts from solutions of water – salt(s) – polar organic THI due to the possible limited mutual solubility of the components.