A three-dimensional multiphase numerical model was used to simulate the infiltration and dissolution of a dense nonaqueous phase liquid (DNAPL) release in two experimental flow cells containing different heterogeneous and well-characterized permeability fields. DNAPL infiltration was modeled using Brooks-Corey-Burdine hysteretic constitutive relationships. DNAPL dissolution was simulated using a rate-limited mass transfer expression with a velocity-dependent mass transfer coefficient and a thermodynamically based calculation of DNAPL-water interfacial area. The model did not require calibration of any parameters. The model predictions were compared to experimental measurements of high-resolution DNAPL saturations and effluent concentrations. The predicted concentrations were in close agreement with measurements for both domains, indicating that important processes were effectively captured by the model. DNAPL saturations greatly influenced mass transfer rates through their effect on relative permeability and velocity. Areas with low DNAPL saturation were associated with low interfacial areas, which resulted in reduced mass transfer rates and nonequilibrium dissolution. This was captured by the thermodynamic interfacial area model, while a geometric model overestimated the interfacial areas and the overall mass transfer. This study presents the first validation of the thermodynamic dissolution model in three dimensions and for high aqueous phase velocities; such conditions are typical for remediation operations, especially in heterogeneous aquifers. The demonstrated ability to predict DNAPL dissolution, only requiring prior characterization of soil properties and DNAPL release conditions, represents a significant improvement compared to empirical dissolution models and provides an opportunity to delineate the relationship between source zone architecture and the remediation potential for complex DNAPL source zones.