In what promises to be one of the most closely watched electoral battles of next year, Ms Pirro, 54, a district attorney from suburban Westchester, kicked off her campaign in Manhattan yesterday.
"I think New Yorkers deserve a senator who is going to be full-time, who is not going to be dissuaded by the needs of other states, maybe primary states, when she votes upon certain issues," she said.
Ms Pirro is a prominent public figure, thanks to frequent television appearances, discussing high-profile crimes.
In her capacity as DA for Westchester she has earned a favourable reputation for her work with battered women and the internet trapping of would-be child molesters. If her presence in the race were not enough to draw national attention, she will also be running in the Republican primary against Richard Nixon's son-in-law, Edward Cox.
In a leader column headlined "For once, election excitement", the New York Times welcomed her entry, saying: "Now we may have a race everybody will be watching."
With Ms Clinton still the presidential candidate of choice for most Democrats for 2008, Ms Pirro intends to concentrate on claims that she is too distracted with her White House ambitions to look after New York.
But Ms Clinton remains popular in the state. An opinion poll last week had her leading Ms Pirro by 63% to 29%. Ms Pirro also has her own spousal liability. Her husband, Albert, is a confessed philanderer and former real estate attorney who served time in prison for tax fraud. Worse still, Ms Pirro co-signed the tax returns.
"There's not any part of my life that's not in that indictment," Ms Pirro complained as she left court on the opening day of the trial in 2000.
However, Michael Edelman, a Republican commentator and a friend of the Pirros, told Associated Press news agency: "Jeanine is going to be judged on her own merits. The people of New York are sophisticated enough to make a distinction between Jeanine and whatever Al may have done in the past. Besides, it [mud-slinging] would backfire. Hillary's husband has been impeached. I don't think she's in any position to bring up husbands."
For all her problems, Ms Pirro is regarded by Republican leaders as the best hope for at least wounding, if not beating, Ms Clinton.
But in order to win over local Republican officials she has had to reverse some of her previously held positions. When she ran for DA in 2001, she said she was in favour of partial-birth abortions. On Tuesday she said that, after reflection, she opposed them except to protect the life of the mother.
Robert Jaffe, deputy director of the abortion rights group, Naral Pro-Choice New York, told the New York Times: "It's a disturbing and desperate attempt to win over the far right of the Republican party, and it won't fool New Yorkers."
The political pedigrees
Jeanine Pirro (54)
Education University of Buffalo and Albany Law School
Career Became a prosecutor more than 25 years ago in Westchester. In 1978, she headed the first domestic violence unit. Chief law enforcement officer of Westchester County since 1994, now serving her third four-year term
Marriage In 1975 to Albert J Pirro, who was recently indicted on 66 counts of federal tax fraud. Paternity suit in 1995 by Jessica Marciano, who claims her 16-year-old daughter is his
'When Mrs Clinton first came to us and said she wanted to be a New Yorker, she asked New York to put out a welcome mat and we did. But now she wants us to re-elect her even though she won't promise to serve out her term and wants to use us as a springboard to the presidency. She's asking us to become her doormat.'
Hillary Rodham Clinton (57)
Education Wellesley College, an elite all-women university, and in 1969 Yale Law School Career
Legal counsel, Nixon impeachment staff (1974), law lecturer, University of Arkansas (1979-80). New York senator since 2001
Marriage To Bill Clinton in 1975; their daughter Chelsea was born in 1980
'I am not some little woman standing by her man like Tammy Wynette'
On Bill: 'A hard dog to keep on the porch'
On the New York Senate race: 'There hasn't been anybody whose life has been picked apart and distorted as much as mine'