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Manalo was baptized a Roman Catholic, but at a young age went into a series of faith hopping. He joined the local spiritist cult, but later joined the Methodist Episcopalian Church after witnessing a debate. He attended their seminary and became a pastor. He later joined the Christian and Missionary Alliance, to which he got attracted to the way their converts were being baptized, which was by immersion.
His ministry led him into a debate with Mr L.V. Finster of the Seventh-day Adventist Church. He lost, and was convinced into joining the Adventists. In his ministry with the Seventh-day Adventist Church, he went into a falling away with the administration with accusations of his moral indiscretion. He started his own Church patterned mostly from the Seventh-day Adventist Church and the Christian and Missionary Alliance. He called it Iglesia ni Cristo.
He has claimed to be the fulfillment of bible prophecy, among which are the ravenous bird of Isaiah 46:11, the shepherd of John 10:16, the fifth angel of Revelation 7:1, etc.
He was married to Tomasa Sereneo , with whom him he had a child who died in infancy. Tomasa herself was afflicted with tuberculosis and died as well. He later married Honorata de Guzman , a fellow Adventist. Their fifth child, Erano Manalo, now heads the Church. Felix Manalo was afflicted with an intestinal disease and died in April 12, 1963.