Siyabonga plays for Pirates, while Thamsanqa is with Amazulu. They have promised to temporarily suspend their relationship in favour of sibling rivalry for this match.
The Durban-born Sangwenis both wear jersey No21.
This will be the second time they face each other after their clubs drew 0-0 at Orlando stadium in the first round in October.
"Thami is my younger brother, but whenever we play, I see him just like any other player - tackles fly," said Sangweni senior.
"If you see us on the field you wouldn't be able to tell we are brothers. This is a game we must win to enhance our chances of successfully defending the league."
Thamsanqa said: "I see Siyabonga as an opponent when we play. Our relationship is temporarily suspended, because we have a job to do.
"Pirates must not expect favours from us. We also need a win to qualify for the top eight."
Thami has regained his appetite for goals, scoring twice in Usuthu's last two matches.
Siyabonga is coming back from a one-match suspension, which will also see goalkeeper Senzo Meyiwa return to the starting line-up.
Meyiwa replaces suspended first choice keeper Moeneeb Josephs.
Meyiwa is over the moon with the prospect of playing in the province of his birth.
"Playing in KwaZulu-Natal is always special because my relatives will not have to travel long distances to watch me in action," said Meyiwa.
With Pirates' promising season derailed by recent setbacks in cup competitions, Meyiwa said Bucs want to defend their league title.
Winger Daine Klate is also back from suspension.
Meanwhile, Wits are confident of bringing high-flying Moroka Swallows down to earth in their match at Dobsonville stadium.
This is despite the fact that the Wits camp resembles a casualty ward, with most of their key players injured.
The injured include Thando Mngomeni, Ryan Chapman, Nyiko Chabangu and Sandile Sibande.
"This is a big challenge because Thando and Ryan are out until next season, but we will put up a big fight," said Wits director George Mogotsi.
"Our coach Roger de Sa has a plan for us to do well in this match. We have promoted several youngsters who will be given a run.
"He gave Zaid Patel a run against Mamelodi Sundowns, and the youngster scored on his debut. Expect more exciting youngsters from our academy."
"Swallows beat us 3-1 in the first round at home. We need to devise a plan to neutralise them," said Mogotsi.
Bloemfontein Celtic have also vowed to beat Free State Stars again this season - this time in their own back yard.
Celtic take a short trip to Namahadi for the Free State derby.
The visitors defeated Stars 1-0 in their first-round match in Botshabelo in October.
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