Police are investigating whether wet weather was a factor in the death of a 28-year-old woman who lost control of her car while driving south on Appin Road about 3pm on Tuesday.
The woman's car collided head-on with a second vehicle before coming to rest in bushland off the notorious section of road, about 1.8 kilometres north-west of Loddons Creek.
The driver of the second vehicle, a 67-year-old woman, was trapped in her car for almost an hour following the crash.
She suffered injuries including a fractured left arm and was flown to St George Hospital in a serious condition.
Campbelltown police inspector Tara Norton said it was a tragic event.
"There's going to be trauma for families across a number of suburbs," she said.
"Unfortunately the weather conditions may have contributed.
"This roadway can be [dangerous] in certain conditions - obviously the rain is something we will need to look at whether or not that was a contributing factor to the accident."
In 2011, the same section of road claimed the life of 21-year-old Ashleigh Connor, who was on her way home to Rosemeadow after her weekly football training session in Wollongong was cancelled due to bad weather.
Tuesday's crash was just metres from a roadside memorial dedicated to Ashleigh.
In March 2014, a Roads and Maritime Services report identified four danger spots for fatal crashes along Appin Road, including a 200-metre section of road where Tuesday's crash occurred.
At the time, there had been a total of 10 crashes in the section - two of which were fatal, with speed being a factor in both.
There were also four crashes that occurred in the section in wet weather.
Tuesday's crash closed Appin Road between Appin and the M1 Princes Motorway for several hours while emergency crews worked to salvage the vehicles.
Gallery and video at llawarramercury.com.au