The Floridan aquifer system is a highly productive carbonate aquifer that provides drinking water to about 10 million people in Florida, Georgia, and South Carolina. Approximately 1.6 million people rely on domestic wells (privately owned household wells) for drinking water. Withdrawals of water from the Floridan aquifer system have increased by more than 500 percent from 630 million gallons per day (2.38 cubic meters per day) in 1950 to 4,020 million gallons per day (15.2 cubic meters per day) in 2000, largely due to increases in population, tourism, and agriculture production. Water samples were collected from 148 domestic wells in the Upper Floridan aquifer in Florida, Georgia, South Carolina, and Alabama during 1998-2005 as part of the U.S. Geological Survey (USGS) National Water-Quality Assessment Program. The wells were located in different hydrogeologic settings based on confinement of the Upper Floridan aquifer. Five networks of wells were sampled con-sisting of 28 to 30 wells each: two networks were in unconfined areas, two networks were in semiconfined areas, and one network was in the confined area. Physical properties and concentrations of major ions, trace elements, nutrients, radon, and organic compounds (volatile organic compounds and pesticides) were measured in water samples. Concentrations were compared to water-quality benchmarks for human health, either U.S. Environmental Protection Agency (USEPA) Maximum Contaminant Levels (MCLs) for public water supplies or USGS Health-Based Screening Levels (HBSLs). The MCL for fluoride of 4 milligrams per liter (mg/L) was exceeded for two samples (about 1 percent of samples). A proposed MCL for radon of 300 picocuries per liter was exceeded in about 40 percent of samples. Nitrate concentrations in the Upper Floridan aquifer ranged from less than the laboratory reporting level of 0.06 to 8 mg/L, with a median nitrate concentration less than 0.06 mg/L (as nitrogen). Nitrate concentrations did not exceed the MCL of 10 mg/L. Statistical comparisons indicated that median nitrate concentrations were significantly different by degree of confinement where the highest median nitrate concentration was 1.46 mg/L for 58 samples from unconfined areas, and by network, where the highest median nitrate concentration was 2.43 mg/L in 28 samples from unconfined areas in southwestern Georgia. Nitrate concentrations in unconfined areas were positively correlated to: (1) the percentage of agricultural land use around the well, (2) the amount of nitrogen fertilizer applied, and (3) the dissolved oxygen concentrations in groundwater. Volatile organic compounds (VOCs) were detected in about 63 percent of all samples. Chloroform, carbon disulfide, and 1,2-dichloropropane were the most frequently detected VOCs. Chloroform, a byproduct of water chlorination, was most frequently detected in unconfined urban areas. Carbon disulfide, a solvent, was most frequently detected in confined areas in southeastern Georgia. Pesticides were detected in about 21 percent of all samples, but were detected in about 69 percent of the 28 samples from unconfined areas in southwestern Georgia. The herbicides atrazine, deethylatrazine, and metolachlor were the most frequently detected pesticides.