Systematic analyses of the formation water and natural gas geochemistry in the Central Uplift of the Tarim Basin (CUTB) show that gas invasion at the late stage is accompanied by an increase of the contents of H2S and CO2 in natural gas, by the forming of the high total dissolved solids formation water, by an increase of the content of HCO3–, relative to Cl–, by an increase of the 2nd family ions (Ca2+, Mg2+, Sr2+ and Ba2+) and by a decrease of the content of SO42?, relative to Cl?. The above phenomena can be explained only by way of thermochemical sulfate reduction (TSR). TSR often occurs in the transition zone of oil and water and is often described in the following reaction formula: ΣCH+CaSO4+H-2O→H2S+CO2+CaCO3. (1) Dissolved SO42? in the formation water is consumed in the above reaction, when H2S and CO2 are generated, resulting in a decrease of SO42? in the formation water and an increase of both H2S and CO2 in the natural gas. If formation water exists, the generated CO2 will go on reacting with the carbonate to form bicarbonate, which can be dissolved in the formation water, thus resulting in the enrichment of Ca2+ and HCO3?. The above reaction can be described by the following equation: CO2+H2O+CaCO3→Ca2++2HCO3?. The stratigraphic temperatures of the Cambrian and lower Ordovician in CUTB exceeded 120°C, which is the minimum for TSR to occur. At the same time, dolomitization, which might be a direct result of TSR, has been found in both the Cambrian and the lower Ordovician. The above evidence indicates that TSR is in an active reaction, providing a novel way to reevaluate the exploration potentials of natural gas in this district.