Pakistan captain Inzamam-ul-Haq returned to the side after recovering from a back injury.
The weather was hot and the pitch looked good for batting. Teams chasing targets have done well in previous One-day matches at the ground.
Both sides showed several changes following a Twenty20 international which South Africa won by ten wickets in Johannesburg Friday.
In addition to Inzamam, leading batsman Mohammad Yousuf and fast bowlers Mohammad Asif and Mohammad Sami returned to the Pakistan team.
For South Africa, Jacques Kallis, Ashwell Prince, Mark Boucher, Andre Nel and Makhaya Ntini were all included after missing the 20-overs match.
Hard-hitting opening batsman Loots Bosman, who had not been expected to feature at the start of the 50-overs series, kept his place after scoring 53 not out off 32 balls Friday.
For both teams, the five-match series is their last before the World Cup in the West Indies next month.
South Africa: Graeme Smith (captain), Loots Bosman, AB de Villiers, Jacques Kallis, Ashwell Prince, Justin Kemp, Mark Boucher, Shaun Pollock, Robin Peterson, Andre Nel, Makhaya Ntini.
Pakistan: Inzamam-ul-Haq (captain), Kamran Akmal, Mohammad Hafeez, Younis Khan, Mohammad Yousuf, Shoaib Malik, Shahid Afridi, Abdul Razzaq, Rana Naved-ul-Hasan, Mohammad Sami, Mohammad Asif.
Umpires: Peter Parker (AUS), Rudi Koertzen (RSA). TV umpire: Karl Hurter (RSA).
Match referee: Chris Broad (ENG)