During the Spanish Civil War (1936–1939) he built up his party into a major political force during the struggles among the supporters of the Republic between Socialists, Stalinists, Trotskyists and Anarcho-syndicalists.

After the Republicans were defeated by the right-wing forces led by Francisco Franco he went into exile, living in Mexico and then in France.

He was Minister of Agriculture and Economy in the first government of Catalonia formed by president Lluís Companys, from January to October 1934.

[4] The growing strength of the Trotskyist POUM (Partido Obrero de Unificación Marxista, Workers' Party of Marxist Unification) encouraged the PCC to enter into negotiations with the liaison committee.

Comorera wrote from prison urging a quick union of the groups, and the PCC joined the committee in the first half of January 1936.

When the Popular Front gained power in February 1936 Comorera was released and returned to the Ministry of Agriculture and Economy.

[3] Comorera led the USC into unification with the Proletarian Catalan Party (Partit Català Proletari) in April 1936, followed by formation in July 1936 of the Unified Socialist Party of Catalonia (Partit Socialista Unificat de Catalunya, PSUC) Comorera was appointed PSUC secretary general.

He was active in the movement to unify the Anarchist Confederación Nacional del Trabajo (CNT) and the PSUC, and attended plenary meetings of the Communist Party of Spain (Partido Comunista de España PCE).

[3] At the end of November 1936 the Trotskyist POUM denounced the Soviet Union for preventing them from joining the Madrid Defense Council.

On 13 December 1936 Comorera said, "the POUM has initiated a shameful campaign of attacks and slanders against the great proletarian country and friend, using exactly the same arguments as the fascist Germans and Italians."

However, a new "syndical" government was formed on 17 December 1936 that excluded POUM members and included Comorera, Rafael Vidiella and Miquel Valdés of the PSUC.

[9] An article in the CNT newspaper Solidaridad Obrera on 17 April 1937 stated that "[The] way to prevent the sacrifices of our comrades from being reduced to naught is... to create an army that will guarantee victory in the war and the Revolution and to remove Comorera, Aiguadé,[a] Rodríguez Salas,[b] etc.

[3] The Spanish Communist leader Pedro Checa died in Mexico on 6 August 1942 due to complications from an appendectomy.

[16] The guard of honor for his body consisted of Comorera, Antonio Mije, Ángel Álvarez and Federico Melchor.

[15] Comorera formed his own organization and newspaper, while saying he remained loyal to Stalin and hostile to the "degenerate traitor" Tito.

[15] His own daughter, Nuri Comorera Santana, denounced him as a traitor in the PSUC journal published in Paris in March 1950.

[24] Comorera took refuge in Cerdanya, then secretly moved to Spain in April 1951 where he settled in Ripoll under a false name.