But he was struck down by illness to die on March 25, 1525 at the age of 59 in the unstable conditions such as an estrangement of his vassal Kageharu NAGAO, and struggles with the Ogigayatsu-Uesugi family Tomooki UESUGI, the Gohojo clan of Sagami Province Ujitsuna HOJO and the Takeda clan of Kai Province Nobutora TAKEDA for many years.
しかし家臣長尾景春の離反、扇谷上杉家の上杉朝興や相模国後北条氏の北条氏綱、甲斐国武田氏の武田信虎などとの長年の抗争による不安定な情況の中、病に倒れ、大永5年（1525年）3月25日、59歳で死去する。