With almost half the vote in, Knoll led her closest rival, Allegheny County Recorder of Deeds Valerie McDonald Roberts, by about a 4-1 ratio.
Also running in the Democratic primary race were William Hall 3d, a retired builder from Northampton County, and Dauphin County-based political activist Gene Stilp.
Republican candidate Jim Matthews of Montgomery County ran unopposed.
Hall was not ready to call it quits.
"If Catherine Baker Knoll wins, it is not fair to the people of Pennsylvania. She is not qualified to be governor," said Hall.
In the last two administrations, the lieutenant governor has had to take over the role of governor, and many have questioned Knoll's abilities.
Knoll, 75, was elected the first female lieutenant governor in state history in November 2002, despite criticism about her age and fitness for office.
The former state treasurer has three statewide general-election victories to her name in a political career spanning almost 20 years.
In 2002, Knoll overcame eight challengers to win the Democratic primary. This time she proved her critics wrong again.
Knoll ran with Democratic Party endorsement, but without the endorsements of the state's major newspapers and without the support of some county parties, including in Bucks County, where some Democrats openly campaigned against her at the polls.
Knoll was criticized during her first term for several high-profile stumbles, among them misidentifying Gov. Rendell as "Edward G. Robinson," and showing up uninvited at a Marine's funeral with her business card in hand.
"The story of her career; everybody says can't do it," said Knoll's campaign manager Jeff Coyne. "It gets her more invigorated."
Knoll's victory helps Rendell, who endorsed her this year, but did not in 2002, because she enjoys huge popularity among seniors in the state with the second-oldest population and brings the all-important western balance to the ticket.
Contact staff writer Amy Worden at 717-783-2584 or firstname.lastname@example.org.