Vila Real de Santo António is a city, civil parish, and municipality in the Algarve, Portugal. The population in 2011 was 19,156. It is one of the few municipalities in Portugal without territorial continuity: its territory comprises two parts, with the municipal seat located in the eastern part. Both the city and the municipality are the southeasternmost of Portugal. Vila Real de Santo António was founded after the 1755 Lisbon earthquake, and largely expanded in 1774 using the same architectural and construction techniques employed in the reconstruction of Lisbon after the disaster.

The city is situated next to the Guadiana river. Before the construction of the Guadiana International Bridge (in its neighboring upstream municipality of Castro Marim) it used to be the easiest access to Portugal from Andalusia (via ferry from the Spanish city of Ayamonte across the river). Nevertheless, international movement of people and goods is still intense and much visible in the city.