Bremen travel to Hamburg's HSH Nordbank Arena for a place in the German Cup final on May 30th at Berlin's Olympic Stadium, while 24 hours earlier on Tuesday, Bayer Leverkusen face minnows Mainz in the other semi-final.
But the Bundesliga rivals have also drawn each other in the UEFA Cup semi-finals and will meet each other over two legs - first at Bremen's Weserstadion on Thursday April 30, then in Hamburg on May 7.
If Hamburg are victorious against Bremen in the DFB Cup, and then beat them over two legs, they will face the winner of the other semi-final between Dynamo Kiev and Shakhtar in the UEFA Cup final in Istanbul on May 20.
But Hamburg face nine fixtures in five weeks and with six league games left, Martin Jol's side are level on points with Bayern Munich and are three behind Bundesliga leaders Wolfsburg.
Hamburg then face Bremen again in the Bundesliga at the HSH Nordbank Arena on May 10 in a bid to over-haul Wolfsburg and deny Bayern a consecutive league title.
Last Thursday night at the sold out City Of Manchester stadium, a 1-2 defeat was enough to see Hamburg beat Manchester City 4-3 on aggregate and put them through to their first European semi-final in 26 years.
But striker Mladen Petric admits the work-load is taking its toll as his side prepare for their DFB semi-final.
"With so many games in quick succession, it is difficult to keep playing well," said Petric after scoring both goals in Sunday's 2-1 win over Hannover to ensure they stay third in the Bundesliga. "But we have done very well to get this result, it was important to get the win (over Hannover)."
Hamburg's coach Jol said he was pleased his side produced a result against Hannover as they prepare for bigger games against Bremen.
"It was gratifying that my players did the same job they needed to do against Hannover as they will need to do against Werder Bremen."