He ran for the presidency of Mexico three times, and his loss in the 1988 Mexican general election to Institutional Revolutionary Party (PRI) candidate Carlos Salinas de Gortari had long been considered the result of electoral fraud perpetrated by the ruling PRI, later acknowledged by Miguel de la Madrid, the incumbent president at the time of the election.

He studied at Colegio Williams, an all-boys private, secular English-language school located in the old mansion of Porfirio Díaz's finance minister, José Yves Limantour, that has a rigorous academic curriculum.

Both were active in the Movimiento de Liberación Nacional (MLN, Movement of National Liberation), which sought international support for Cuba following its 1959 revolution, as well as to affect domestic politics in Mexico, particularly the need for democracy in the PRI and decentralization of power.

The elections became extremely controversial, and even though some declare that Salinas won legally, the expression se cayó el sistema became a colloquial euphemism for electoral fraud.

"[9] The following year (5 May 1989), Cárdenas and other leading center-left and leftist PRI politicians, including Francisco Arellano-Belloc, formally founded the Party of the Democratic Revolution (PRD).

Cárdenas's poor showing at the polls may reflect the Mexican public's desire for stability via the long-time ruling party remaining in office.

In the assessment of Enrique Krauze, "the events in Chiapas probably cost the PRD and its candidate, Cuauhtémoc Cárdenas—who had no involvement with the Zapatista uprising—the votes of many Mexicans uneasy with the return of the past.

"[11] Despite the PRD's electoral results, they were part of the 1996 negotiations between the PRI and the conservative National Action Party (PAN) on institutional reform.

[13] In 1996, the PRD was choosing a new party president, Cárdenas's ally Andrés Manuel López Obrador, who went further and sought a political alliance with the Zapatistas.

[14] In 1997, he was the PRD's candidate for the newly created post of Head of Government (Jefe de Gobierno) of the Federal District – effectively, a role lying somewhere between that of Mexico City's mayor and a state governorship.