The N2 highway close to Somerset West was closed briefly on Sunday evening after several motorists were attacked.
Cape Town law enforcement spokesperson Wayne Dyason said some vehicles were stoned, which resulted in the injury of two drivers who were taken to hospital.
He added a petrol bomb was also thrown at a car, causing minor damage.
City of Cape Town traffic services spokesperson Maxine Jordaan said the N2 was closed at Broadlands Avenue and Onverwacht Street as well as Sir Lowry's Pass due to protest action.
Roads were re-opened afterwards with the police monitoring the area.
The reason for the protest was not immediately clear.
Traffic was backed up on the N2 on Sunday afternoon as motorists returned home after the long weekend.
Western Cape traffic chief Kenny Africa said there was a high volume of traffic from the Houwhoek and Sir Lowry's passes.
The N2 close to Somerset West has been a hot spot for violence this week.
On Saturday, a truck assistant suffered burn wounds to his face and hand after a bread truck was petrol-bombed on the corner of the N2 and Onverwacht Street in Lwandle.
"The driver and his two passengers were on the corner of Onverwacht Street and the N2 in Lwandle waiting for the robot to turn green when three unknown men approached them and threw a petrol bomb at the truck and then [ran] away," the police said in a statement.
A case of malicious damaged to property was opened and is being investigated by detectives.
Last week, a truck driver broke his collarbone after his truck was petrol-bombed. A video shows two truck drivers sitting inside a stationary vehicle, when the petrol bomb is thrown. Two men can be fleeing the scene on Broadlands Avenue in Somerset West.
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