Although the game is not a Ranfurly Shield challenge - after Otago went close but came up short against Wellington last Friday night - the Donald Stuart Memorial Shield is at stake in the match at Carisbrook.
Otago holds the shield after a last-minute penalty goal by Chris Noakes secured the win last year.
Otago Rugby Football Union chief executive Richard Reid said he was hopeful a good crowd would turn up.
Although Otago did not beat Wellington it did show it was competitive, and had displayed some spirit.
Southland had a hard-fought 16-6 win over Waikato in Invercargill on Saturday night to open its Air New Zealand Cup campaign with a win.
"We just want people to turn up and get behind the team.
"We're playing Southland and it is a Highlanders derby and that should generate some interest," Reid said.
He said there was a promising look to the Air New Zealand Cup in the opening round with good crowds for most games.
He did not want to estimate a crowd number for Friday night, but said the team played better with a supportive crowd behind it.
The Otago union had closed some stands at Carisbrook for the coming season, with seats limited to the main stand and the terrace and a small section in the Neville St stand opened up for a family section.
Otago had few injury concerns although prop Sam Hibbard had a calf niggle which forced him off the field last Friday night at half-time to be replaced by Kees Meeuws.
Although the days of the clash between Otago and Southland being a Highlanders trial appear to be over, it should be an important game for hookers Jason Macdonald and David Hall.
Hall was the starting hooker for the Highlanders this year and Macdonald was drafted to the Crusaders, but he played well for the Christchurch-based franchise and appears to be back in form.
The clash between openside flankers Tim Boys and Alando Soakai will create plenty of interest after Soakai won the starting berth for the southern franchise this season, ahead of Boys.
Otago and Southland have clashed 229 times, with 141 victories for Otago, 78 wins for Southland and 10 draws.
