When Argenio ran for re-election in 2000, Negron once again challenged him in the primary, along with David Traill, and received a plurality of the vote, thus necessitating another runoff election.

The two also disagreed on health care policy, with Negron suggesting that patients should be able to sue HMOs and announcing that he would sponsor legislation that would allow patients to see specialists without approval from their primary care physician, and Argenio calling Negron's plans a "lawyer's bill of rights.

"[9] Ultimately, Negron narrowly defeated Argenio to win the Republican nomination for the seat, and was unopposed in the general election.

Negron initially planned on running for Attorney General of Florida in 2006, but, citing an inability to compete with former Congressman Bill McCollum in the Republican primary, dropped out of the race.

[11] Over the course of the campaign, the Sarasota Herald-Tribune endorsed Mahoney over Negron, citing his business experience and his moderate issue positions.

[14] He faced Bill Ramos, the Democratic nominee, in the general election, and campaigned on protecting the St. Lucie River, promoting biotechnology, and increasing education spending, declaring, "I'm looking forward to working hard to continue building on the foundation that Senator Ken Pruitt built with the research coast.

[17] The Palm Beach Post endorsed Negron, praising him as one of the legislature's "most influential Republican leaders" and "one of his party's more thoughtful and moderating voices."

They noted, however, "We hope Sen. Negron does modify his position on many issues, from the expansion of Medicaid to the need to tax Internet sales to pay for priorities like public education.