Team advisor Helmut Marko last week reiginited speculation about McLaren driver Hamilton's future by admitting the 2008 world champion "must always be a topic" when considering a possible successor for Mark Webber.
"Our philosophy is to have the quickest drivers together in our team," he said.
But Horner told the BBC that a Hamilton-Vettel combination could be a recipe for disaster.
"It's difficult to see how you could have two drivers of Lewis' and Sebastian's calibre under one roof. There tends to be fireworks as we saw with Fernando Alonso and Lewis (at McLaren)," he said.
The comments could be interpreted as Horner believing that 34-year-old Webber is not of the "calibre" of Hamilton or Vettel.
Asked if that is what he meant, Horner insisted: "Absolutely not. They (Vettel and Webber) are at different stages of their careers and they complement each other."