Masamoto was a son of Hosokawa Katsumoto and was appointed kanrei in 1486. He lost the post for a brief period to Hatakeyama Masanaga but recovered his position. When the shôgun Ashikaga Yoshihisa died childless in 1489, Masamoto supported the nomination of Ashikaga Yoshizumi as successor. In the event, Ashikaga Yoshitane was chosen. Masamoto was concerned that, given Yoshitane's closeness with Hatakeyama Masanaga and his own objections to Yoshitane's rise, the post of kanrei would be returned to Masanaga. In 1493 Yoshitane had led troops to support Hatakeyama Masanaga in his struggles with a rival branch of the Hatakeyama clan. Masamoto committed forces to the rival Hatakeyama and Masanaga and Yoshitane were defeated. Masanaga took his own life and Yoshitane was returned to Kyoto as a prisoner. Masamoto sent Yoshitane into exile and replaced him with Ashikaga Yoshizumi, whom Masamoto went on to use as a puppet. That same year, he launched a campaign against his opponents within Yamashiro province. Being childless, Masamoto (who is thought to have been a homosexual) adopted a number of sons (Hosokawa Sumiyuki and Hosokawa Sumimoto). The Hosokawa retainers began to align with one of the young men against the other. In 1504 Masamoto destroyed the rebellious Yakushiji Motoichi (a supporter of Sumimoto) and in 1506 was threatened by an army led by Miyoshi Yukinaga (another of Sumimoto's supporters). In 1507, Kôsai Motonaga, a friend to Sumiyuki, betrayed Masamoto and along with Sumiyuki attacked Masamoto's home. Masamoto was murdered while taking a bath.
- Initial text from Sengoku Biographical Dictionary (Samurai-Archives.com) FWSeal & CEWest, 2005