This article is about the Bolivian city. For other cities named Santa Cruz, see the disambiguation page

Santa Cruz de la Sierra, commonly known as simply Santa Cruz, is the second largest city in the Republic of Bolivia with a population of roughly one million residents. It is also the capital city of the Department of Santa Cruz. Located in the eastern part of the country at 416m above sea level, the city, though usually warm, experiences chill winds that blow from the Argentine pampas called surazos.

Santa Cruz de la Sierra was first founded on February 26, 1560 by Ñuflo de Chávez who gave the new settlement its name, which means "Holy Cross of the Mountains," in honor of his beloved native city in Extremadura, Spain. The original settlement was actually 220km east of its current location, only a few kilometers south of today's San José de Chiquitos. After conflicts with natives the town was moved to its present position on the banks of the Piraí River in 1592. Some remains of the original settlement can be visited in the Santa Cruz la Vieja (= Old Santa Cruz) archeological site south of San José de Chiquitos (which was founded as a Jesuit mission in 1792).

Santa Cruz is connected by railway to Argentina and Brazil, and connected by a road built in the 1950s to Trinidad, Cochabamba and the Chaco badlands. It is also the home of Viru Viru International Airport, one of the largest airports in Bolivia.

As the city was fairly isolated until the early 20th century, Santa Cruz has much colonial architecture, including a 16th century cathedral and numerous Jesuit missions, and a World Heritage listed Inca fortress called El Fuerte de Samaipata.