Around two million fish have died in the Chesapeake Bay area in Maryland, just days after two similar incidents elsewhere in the US baffled scientists.
Officials are now trying to find out what happened.
Maryland Department of the Environment spokeswoman Dawn Stoltzfus told Sky News Online that at the moment it does not look like pollution is to blame.
She said: “The dead fish are mainly juvenile spot fish, and they can’t survive very cold water temperatures. Typically they should have left the bay by now.
“Our working theory, that looks pretty strong, is that it’s been caused by cold water stress.”
This mass “fish kill”, as it is called, happened after water temperatures plunged to near record lows in the area in late December, but scientists have yet to prove conclusively that this was the cause.
Elsewhere in the US, large numbers of sudden bird and fish deaths have perplexed biologists.
Just days ago, an estimated 500 small birds, mostly blackbirds, fell out of the sky in Louisiana.
On New Year’s Eve in Arkansas, thousands of the same species were found, followed by the discovery of around 100,000 dead fish in a river about a hundred miles away.
Officials think that power lines may be to blame for the Louisiana deaths, and fireworks or lightning could have been responsible for what happened in Arkansas.
The events are not being linked, but similar scenarios across the world are adding to the mystery.
Officials reported around 50 jackdaws had been found dead on a street in Sweden, and other unexplained mass fish deaths have occurred recently in Brazil and New Zealand.
Large fish kills have happened before in Chesapeake Bay, most notably in 1976 and 1980. Officials acknowledged that the most recent incident is the biggest since those events.