The Sowetan on Tuesday quoted Ms Zille as saying: "Zuma is a self-confessed womaniser with deeply sexist views, who put all his wives at risk by having unprotected sex with an HIV-positive woman."
Self-proclaimed polygamist Mr Zuma was acquitted of rape in 2006 when he conceded having unprotected sex with his accuser, an HIV-positive family friend, but said he showered afterwards to prevent infection.
African National Congress spokesperson Jessie Duarte said in a statement: "Even by Zille's standards of personal invective, this latest attack is an unprecedented example of Zuma-hate. Zille's outburst is deeply offensive and should be roundly condemned."
The ANC Youth League then waded in with a statement threatening to take militant action against Ms Zille if she continued to talk "hogwash".