Guatemala's major diplomatic interests are regional security and, increasingly, regional development and economic integration. The Council of Central American Ministers of Trade meet on a regular basis to work on regional approaches to trade issues. They signed a Trade and Investment Framework Agreement (TIFA) with the U.S. in 1998, and they currently are negotiating a free trade agreement with the United States. Guatemala joined Honduras and El Salvador in signing a free trade agreement with Mexico in 2000, which went into effect the following year. Guatemala also originated the idea for, and is the seat of, the Central American Parliament (PARLACEN).

Guatemala participates in several regional groups, particularly those related to environment and trade. For example, President Clinton and the Central American presidents signed the CONCAUSA (Conjunto Centroamerica-USA) agreement at the Summit of the Americas in December 1994. CONCAUSA is a cooperative plan of action to promote clean, efficient energy use; conserve the region's biodiversity; strengthen legal and institutional frameworks and compliance mechanisms; and improve and harmonize environmental protection standards.

Guatemala has a longstanding claim to a large portion of Belize; the territorial dispute caused problems with the United Kingdom and later with Belize following its 1981 independence from the U.K. In December 1989, Guatemala sponsored Belize for permanent observer status in the Organization of American States (OAS). In September 1991, Guatemala recognized Belize's independence and established diplomatic ties, while acknowledging that the boundaries remained in dispute. In anticipation of an effort to bring the border dispute to an end in early 1996, the Guatemalan Congress ratified two long-pending international agreements governing frontier issues and maritime rights. In 2001, Guatemala and Belize agreed to a facilitation process led by the OAS to determine the land and maritime borders separating the two countries. National elections in Guatemala have put a temporary halt to progress in this forum, but discussions are expected to resume in 2004.