This year, teams face the challenge of mastering turbocharged 1.6-litre V6 powertrains, with technical chiefs anticipating teething issues when the new technology is given its first mileage during pre-season testing.
Concerns have also been raised over the new 100kg fuel limit per race, which is set to be pushed to the limit around the streets of Melbourne, a circuit traditionally severe in terms of consumption levels.
Speaking in a wide-ranging interview on the Bloomberg TV channel, Horner explained: "I think you could see a very high retirement rate, maybe even 50 percent [of the field failing to finish] in the first race.
"Petrol is a challenge because we are limited to 100kg to start the Grand Prix with, but I think more reliability issues in the early races are going to be a key factor. And we only have five engines for the whole year."
Horner added that there is a high possibility of the better funded teams being even further ahead of their midfield and backmarker counterparts this season, given the cost involved in building packages to the new rule set.
"The differences between the teams will be bigger," he said. "Whenever there is a reset, the teams that have the investment, that have the resources and the facilities will always turn up with a more advanced product."
When asked if a two-tier series could be the overall result, Horner responded: "I think it could be. That is why stability is so important, as if you have stability then the grid concertinas, and it is down to details.
"The regulations we have for this year are a definite game changer."