There has been an accident on Campbelltown Road, with heavy traffic and diversions in place in Bow Bowing.
Police have confirmed that three people have died, and another two people have been taken to hospital.
A male driver, 74, and two passengers were treated by NSW Ambulance paramedics, but died at the scene.
A 76-year-old woman and a 45-year-old man were also in the car. They were taken to Liverpool Hospital.
The driver of the truck, a 59-year-old man, has been taken to Campbelltown Hospital for mandatory testing.
Early footage appears to show a car which has ploughed into a fence on the side of the road.
The accident saw a truck and car collide, with two people trapped initially.
The incident happened at roughly 11.30am, with the Crash Investigation Unit, RMS and emergency services currently at the scene.
Motorists are advised to expect delays and exercise caution, with Campbelltown Road closed in both directions between St Andrews Rd and Williamson Rd.
If travelling in this area, use the Hume Highway instead Campbelltown Road.
Buses have been diverted away from Campbelltown Road via local streets.
Four stops have been missed as a result.