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The 35-year-old added an invaluable 121 runs with AB de Villiers (61) and another 61 for the second wicket with Hashim Amla (62) after South Africa won the toss and batted at the Dubai Stadium.
Kallis, who scored 66 in South Africa's eight wicket win in the first match in Abu Dhabi, hit four boundaries before he cut leg-spinner Shahid Afridi straight into the hands of Wahab Riaz in the 39th over.
When Kallis reached 81, he completed 11 000 one-day runs in his 307th match. He became the sixth batsmen to score 11 000 or more runs in the 50-over format of the game.
India's Sachin Tendulkar (17598), Sri Lankan Sanath Jayasuriya (13428), Australian Ricky Ponting (13082), Pakistan's Inzamam-ul-Haq (11739) and Indian Sourav Ganguly (11363) are the others to have achieved the 11,000-run mark.
The fifth and final match, left intriguing after both teams won two matches each, started on a dramatic note when Pakistan team management said wicket-keeper Zulqarnain Haider had gone missing from team's Dubai hotel.
Pakistan Cricket Board later said Haider, who scored a match-winning 19 not out to help Pakistan win the fourth match on Friday, left for London after receiving threats from an unknown person.
Without Haider, Pakistan had to hand the wicket keeping gloves to Umar Akmal, one of three changes in the side which also saw Mohammad Yousuf and Shahzaib Hasan brought in.
Graeme Smith (14) and Amla started at brisk pace to take their team to 37 inside five overs, when Akhtar removed the South African skipper, caught by Afridi.
Amla, when on 23 reached 1,000 one-day runs in 2010, hit eight boundaries and a six to reach his tenth fifty. He hit one more four before holing out to Afridi after his brisk 47-ball knock.
Kallis and De Villiers took the score to 219 before Pakistan took three wickets in the space of nine runs, removing Kallis, De Villiers and Colin Ingram (one).
De Villiers hit five boundaries during his 72-ball knock.
JP Duminy (59 not out) and Johan Botha (28 not out) put on a rapid-fire 89 off just 65 balls for an unbroken sixth wicket stand. Duminy hit eight boundaries during his 41-ball knock.
Scoreboard:
Hashim Amla c Akhtar b Afridi 62
Graeme Smith c Afridi b Akhtar 14
Jacques Kallis c Riaz b Afridi 83
A.B. de Villiers c Khan b Hafeez 61
J.P. Duminy not out 59
Colin Ingram run out (Abdur Rehman) 1
Johan Botha not out 28
Extras: (1b, 5w, 3lb) 9
TOTAL: (for five wickets) 317
Overs: 50.
Did not bat: Robin Peterson, Morne Morkel, Dale Steyn, Charl Langeveldt.
Fall of wickets: 1-37, 2-98, 3-219, 4-227, 5-228.
Bowling: Shoaib Akhtar 7-0-77-1, Abdul Razzaq 3-0-18-0, Abdur Rehman 10-0-33-0 (1w), Shahid Afridi 10-0-59-2 (1w), Mohammad Hafeez 10-0-47-1 (1w), Wahab Riaz 8-0-64-0 (2w), Younis Khan 2-0-15-0.
Toss: South Africa.
Umpires: Umpires Daryl Harper, Australia, and Nadeem Ghauri, Pakistan.
TV umpire: Zameer Haider, Pakistan. Match referee: Andy Pycroft, Zimbabwe.