The federal prosecutor's office said the driver, the fare collector and two passengers were slain in the attack yesterday in Cuscatlan department, about 13 miles (21 kilometres) northeast of San Salvador.
Investigators say at least five presumed gang members got on the bus as it began its route toward the capital, attacked the driver and then turned their guns on the passengers.
The wounded were taken to a hospital for treatment, and authorities were searching for the assailants.
Service resumed by the weekend, days after authorities arrested an alleged gang leader believed to be responsible for the attacks and intimidation.
Also yesterday, police reported that an officer was killed in an armed ambush while patrolling in the rural municipality of San Juan Nonualco, southeast of the capital.