Rafael van der Vaart and Marcell Jansen have been told they do not have futures with Hamburg.
Both will be out of contract in the summer and neither will be offered new terms, the Bundesliga club's director of sport Dietmar Beiersdorfer said.
Meanwhile, Heiko Westermann and Slobodan Rajkovic face uncertainty over their futures.
"Rafael and Marcell know that we are not going to hold any talks with them over contract extensions," Beiersdorfer told his club's official website.
"With Heiko and Slobodan, we've left it open. We've postponed a decision and told the players this.
"The players have assured us that ensuring Hamburg avoid relegation is the absolute priority and that they will put everything into this."
It is not yet clear whether Van der Vaart, 32, will continue his career elsewhere, but he has been offered another role at Hamburg when he does hang up his boots.
"Yes, we've spoken about that," Beiersdorfer said. "Rafael is one of the best and most significant players in Hamburg's recent history.
"We want to give him the opportunity to return here after his playing career. We'll discuss what sort of role that could be at the given time."
Van der Vaart has made 192 appearances for Hamburg over two spells, scoring 66 goals.
Hamburg, who have never been relegated from the Bundesliga, are currently third from bottom in the relegation playoff position and just a point above the automatic drop zone.