More than 600 stable isotope analyses from veins and their metasedimentary host rocks from the Ouachita orogenic belt of Arkansas and Oklahoma provide an opportunity to study fluid-rock interaction processes associated with vein formation during deformation and low-grade regional metamorphism. The δ18O values of vein quartz vary from 16.0 to 26.4‰, whereas coexisting host rocks have a greater range from 12.9 to 27.4‰. The oxygen isotopic compositions of quartz vein versus those of the coexisting host rocks follow an array described by δ18Ovein quartz ≈ δ18Owhole rock + ε, where ε ≈ 8–0.3(δ18Owhole rock). This relationship emphasizes the dependence of δ18O values of vein quartz on host-rock oxygen isotopic composition. The ε term empirically monitors the difference between the quartz-water fractionation factor and the compositional dependence of the bulk-rock–water fractionation factor. Vein-quartz–host-rock Δ18O fractionations are ∼0‰ in chert, novaculite, quartzite, and siliceous shale and typically between 1 and 4‰ in sandstones and shales. In quartzite and sandstone units that are bounded by shales and associated with significant quartz-crystal deposits, vein-quartz–host-rock fractionations are often unusually large, near 7‰. Quartz-calcite oxygen isotope geothermometry indicates that veins from the Ouachita Mountains formed over a temperature interval of 100 °C, consistent with fluid-inclusion temperatures previously obtained from quartz crystals. Individual quartz veins are homogeneous, with <0.4‰ variation, for all vein orientations at all scales, even though vein formation occurred over a temperature interval in which quartz-water fractionation varies by 5‰. This homogeneity highlights the insensitivity of vein-quartz δ18O values to temperature when veins form under rock-buffered conditions. The similarity between vein and host-rock δ18O values in quartz-rich lithologies, and between vein and host-rock δ13C values in calcite-bearing rocks, indicates that diffusion was an important mass-transport mechanism. The variability in δ18O values between calcite-bearing veins and host rocks and large vein-quartz–whole-rock fractionations in some sandstones and quartzites indicates that advection also played a major role in mass transport associated with vein formation. This inference leads to the interpretation that veins from the Ouachita Mountains formed by a combined diffusion-advection process, whereby 18O and 13C from the host rock was transported into the veins with the assistance of a rock-buffered fluid on outcrop scales of 10–100 m.