The union of the crowns of Spain and Portugal in 1580 affected the relations between Macao and Manila, and gave rise to new possibilities of cooperation and mutual trade. In spite of the existence of a demarcation line right in the middle of the China Seas, which kept the Castilians away from the Portuguese sphere of influence in Asia, several captain-merchants from Macao carried on business in the Philippines, and some of them even took residence in Manila in order to participate in the trade of the Spanish galleons bound to Acapulco. The Portuguese were successful in building up a transpacific network which included the Indian subcontinent, Mexico and Brazil, reaching as far as Africa and Europe. The growth of the Iberian commerce in the Philippines determined a change in the structure of the triangular trade between Fujian, Kyushu, and Luzon, and stimulated the circulation of gold and silver to Japan. The Macanese captain-merchants also contributed to the development of new trade networks across the China Seas, and became the agents of many Spanish officials and Japanese warlords. At the beginning of the 17th century the Macao-Manila route became essential to the maintenance of the Spanish presence in the Philippines and on the whole to the survival of the Habsburg Empire in Asia. My paper will take in exam the trade relations between the port-cities of Macao and Manila from the late sixteenth century to the early decades of the seventeenth century. It will analyse the political and economic role of the Macao-Manila route throughout the period of the Iberian Union (1580—1640), according to the developments of the Sino-Japanese trade network via Luzon and the fight against the Dutch and English in East and Southeast Asia.