Now the man who was captain of the 2005 tour party to New Zealand will lead the Lions for the fifth time in his career as he makes his 11th appearance for the tourists on his third major tour.
O'Driscoll will form a centre partnership with Jamie Roberts, who is one of three players retained from the starting line-up from Saturday's 37-25 opening victory over the Royal XV. The others are wing Tommy Bowe and back row man David Wallace, who switches from No8 to openside flanker.
There are a further five players in the starting line-up who were used as replacements in Phokeng - Mike Phillips, Lee Mears, Phil Vickery, Alun-Wyn Jones and Jamie Heaslip - while Shane Williams drops from the team to the bench.
"The matchday squad contains five players making their British & Irish Lions run-on debuts while a further six debutants are on the bench. Everyone is also delighted that Brian O'Driscoll, the Irish Grand Slam skipper, will lead the team against the Golden Lions," said tour manager Gerald Davies.
The selection means that of the 36 players the Lions took to South Africa, only Leinster centre Luke Fitzgerald and Munster lock Donncha O'Callaghan will not have been used in the opening two matches.
The Golden Lions represent the old Transvaal and Gauteng Lions teams that have faced the British & Irish Lions 17 times since 1891. They have a reunion on the eve of Wednesday night's fixture for the Transvaal side that beat the Lions in 1968 and have the best record of any South African team against the tourists with seven victories and a draw.
Head coach Ian McGeechan knows it is going to be a step up in class from the opening fixture, but is happy with his side's preparations.
"The starting XV is very different to the one that played against the Royal XV on Saturday," he said.
"There are only three players backing up from that match, although six of the replacements have been promoted to the starting XV. This is in line with the policy that all players will play a full match in the first three matches on tour.
"The team has a very solid core with Brian O'Driscoll, Stephen Jones, David Wallace, Phil Vickery and Gethin Jenkins, who are all very experienced internationals and previous Lions tourists.
"David Wallace now has the opportunity to play at openside flanker following his selection at No 8 against the Royal XV. Stephen Jones who was a replacement in the last match, but did not get a run, links-up with his Welsh team-mate and scrum-half, Mike Phillips, giving the team an experienced halfback combination.
"The team has trained well. We have worked on several key areas following the first match, which has given us a base on which to keep developing our game."
British & Irish Lions (vs Golden Lions)
15. Rob Kearney (Leinster/Ireland)
14. Tommy Bowe (Ospreys/Ireland)
13. Brian O'Driscoll (Leinster/Ireland)
12. Jamie Roberts (Cardiff Blues/Wales)
11. Ugo Monye (Harlequins/England)
10. Stephen Jones (Scarlets/Wales)
9. Mike Phillips (Ospreys/Wales)
8. Jamie Heaslip (Leinster/Ireland)
7. David Wallace (Munster/Ireland)
6. Tom Croft (Leicester Tigers/England)
5. Alun-Wyn Jones (Ospreys/Wales)
4. Nathan Hines (Perpignan/Scotland)
3. Phil Vickery (London Wasps/England)
2. Lee Mears (Bath/England)
1. Gethin Jenkins (Cardiff Blues/Wales)
16. Ross Ford (Edinburgh/Scotland)
17. Euan Murray (Northampton Saints/Scotland)
18. Stephen Ferris (Ulster/Ireland)
19. Andy Powell (Cardiff Blues/Wales)
20. Harry Ellis (Leicester Tigers/England)
21. James Hook (Ospreys/Wales)
22. Shane Williams (Ospreys/Wales)