The weathering of carbonate rocks with sulfuric acid releases carbon dioxide (CO2) to the atmosphere, offsetting the CO2 drawdown from carbonic acid weathering of silicates thought to regulate global climate. Quantifying CO2 release from sulfuric acid weathering requires the partitioning of riverine sulfate between its two main sources: sedimentary sulfate and sulfide. Although the sulfur (d34S_SO4) and oxygen (d18O_SO4) isotope ratios of sedimentary sulfates (gypsum and anhydrite) of different ages are well constrained, the d34S of sulfide minerals is highly variable, restricting the utility of d34S for partitioning sulfur sources. Here, we use oxygen isotope ratios in the river water (d18O_w) and sulfate molecules (d18O_SO4) to partition the fraction of sulfate and associated uncertainty delivered by the oxidative weathering of pyrite (f_pyr). The partitioning is illustrated using the Mekong River, one of the world's largest river basins, presenting new d18O_SO4, d18O_w and dS_SO4 data collected on 18 tributaries and 6 main stem sites over two field seasons at peak flux. The geological, geomorphological and climatic diversity of the Mekong River Basin make it an ideal field site to quantify the role of sulfuric acid weathering and its implications for the carbon cycle. There is a 12 per mil range in both the difference between d18O_SO4 and d18O_w (Delta_SO4-w) andd34S in the river waters of the basin. In the Mekong tributaries, sources of sulfate are highly variable with the fraction of sulfate derived from pyrite oxidation (f_pyr) ranging from 0.19 to 0.84. In the mainstem, f_pyr reflects the flux-weighted mean of these tributary inputs, with 56+/-7% (1sigma) of the sulfate delivered to the ocean at the Mekong mouth being derived from the oxidative weathering of pyrite. As a result, we estimate that ~70% of CO2 consumed through silicate weathering in the Mekong basin is offset by the release ofCO2 via the dissolution of carbonates by sulfuric acid.