A group of prominent Republican and Democratic lawmakers on Wednesday introduced federal legislation that would prohibit companies that own drug middlemen or health insurers from also owning retail pharmacies or those that mail prescriptions to patients. If enacted, the legislation would break up giant health care conglomerates like UnitedHealth Group and CVS Health.

The legislation is the most aggressive legislative effort in recent years to target those drug middlemen. Known as pharmacy benefit managers, or P.B.M.s, they are companies hired by employers and government programs to oversee their prescription drug benefits. The three largest — CVS Health’s Caremark, Cigna’s Express Scripts and UnitedHealth’s Optum Rx — collectively control 80 percent of prescriptions in the United States.

It’s not clear whether the legislation will gain traction. While there has been a bipartisan push to rein in the largest P.B.M.s with legislation requiring more transparency and modest changes to pricing practices, those bills have stalled in Congress and have been met with tremendous resistance from the powerful health care lobbies. The new legislation signals a renewed effort by lawmakers on both sides of the aisle to take on the issue.

“P.B.M.s have manipulated the market to enrich themselves — hiking up drug costs, cheating employers and driving small pharmacies out of business,” one of the sponsors of the legislation, Senator Elizabeth Warren, Democrat of Massachusetts, said in a statement.

Senator Josh Hawley, Republican of Missouri, is the co-sponsor of the Senate bill. A companion bill is being introduced in the House.

The New York Times has reported on how the benefit managers have prioritized their own interests above those of patients, employers and taxpayers.