Santo Domingo de Guzmán, population 2,061,200 (2003), estimated 2,253,437 in 2006, is the capital and the largest city of the Dominican Republic. The city is located at 18°30′N 69°59′W, on the Caribbean Sea, at the mouth of the Ozama River. It is the oldest continuously inhabited European settlement in the Americas, and was the first seat of Spanish colonial rule in the New World.Bartholomew Columbus, brother of Christopher Columbus, founded Santo Domingo, which is today the oldest European city in the New World. In reality the city dates back to 1496, the period when the first Europeans settled there, although officially it was founded on August 5, 1498. The original layout of the city and a large portion of its defensive wall can still be appreciated today throughout the Colonial Zone, declared a World Heritage Site by UNESCO in 1994. The Colonial Zone, bordered by the Río Ozama, has also an impressive collection of 16th century buildings, including palatial houses and majestic churches that reflect the architectural style of the late medieval period.

The city's most important colonial buildings include the Catedral Primada de América, which is the first Catholic Cathedral in America; the Alcázar de Colón, once the residence of Don Diego Colón, the son of Christopher Columbus who became viceroy of the colony; the Monasterio de San Francisco, the ruins of the first monastery in America; the Museo de las Casas Reales, the former Palace of the Governor General and the Palace of Royal Audiences; the Parque Colón, a historic square; the Fortaleza Ozama, the oldest fortress in America; the Panteón Nacional, a former Jesuit now hosting the remains of various renown Dominicans; and the Iglesia del Convento Dominico, the first convent in America.

Throughout its first century, Santo Domingo was the launching pad for much of the exploration and conquest of the New World. The expeditions that led to Ponce de Leon's discovery of Puerto Rico, Hernando Cortes' conquest of Mexico and Balboa's sighting of the Pacific Ocean all started from Santo Domingo.