The three-dimensional structure and dynamics of the combination of the sea breeze and the mistral at the Rhône Valley exit, in southeastern France, have been investigated experimentally and numerically on 22 June 2001. The mistral refers to a severe northerly wind that develops along the Rhône Valley. The exit of this valley is located near the Mediterranean Sea where sea-breeze circulation often develops. The sea breeze and the mistral coexist this day because of the weakness of this mistral event. The event was documented in the framework of the Expérience sur Site pour Contraindre les Modèles de Pollution Atmosphérique et de Transport d'Emissions (ESCOMPTE) field experiment. Several important data sources are used (airborne Doppler lidar, UHF wind profilers, radiosoundings, and surface stations) as well as nonhydrostatic mesoscale simulations. This paper examines the various mechanisms that drive the time and spatial variability of the mistral and the sea breeze in various regions of the Rhône Valley. In the morning, the sea breeze penetrates inland near the western side of the Rhône Valley then moves back because of the reinforcement of the mistral flow caused by the deepening of the leeward surface low due to convection at noon. At midday, the sea breeze penetrates inland in the middle of the Rhône Valley only. In contrast to pure sea-breeze episodes when the sea breeze can extend inland over a horizontal range of more than 150 km, the presence of the mistral prevents the sea breeze from penetrating more than 40 km onshore. In the late afternoon, the sea breeze reaches the eastern side of the Rhône Valley but over a smaller horizontal range because of higher local topography and because the mistral is more intense in this part of the Rhône Valley. The situations of sea-breeze–mistral interactions can have a severe impact on regional air quality. Indeed, the southerly sea breeze, which advects toward the countryside the pollutants emitted from the large coastal city of Marseille, France, and its industrialized suburbs, cannot penetrate far inland because of the mistral blowing in the opposite direction. This leads to the stagnation of the pollutants near the area of emission that is also the most densely inhabited area of the region (over one million inhabitants).