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High-resolution seismic-reflection data collected along the length of the Caloosahatchee River in southwestern Florida have been correlated to nannofossil biostratigraphy and strontium-isotope chemostratigraphy at six continuously cored boreholes. These data are interpreted to show a major Late Miocene(?) to Early Pliocene fluvial-deltaic depositional system that prograded southward across the carbonate Florida Platform, interrupting nearly continuous carbonate deposition since early in the Cretaceous. Connection of the platform top to a continental source of siliciclastics and significant paleotopography combined to focus accumulation of an immense supply of siliciclastics on the southeastern part of the Florida Platform. The remarkably thick (> 100 m), sand-rich depositional system, which is characterized by clinoformal progradation, filled in deep accommodation, while antecedent paleotopography directed deltaic progradation southward within the middle of the present-day Florida Peninsula. The deltaic depositional system may have prograded about 200 km southward to the middle and upper Florida Keys, where Late Miocene to Pliocene siliciclastics form the foundation of the Quaternary carbonate shelf and shelf margin of the Florida Keys. These far-traveled siliciclastic deposits filled accommodation on the southeastern part of the Florida Platform so that paleobathymetry was sufficiently shallow to allow Quaternary recovery of carbonate sedimentation in the area of southern peninsular Florida and the Florida Keys.