Avon and Somerset Police said paramedics found a 30-year-old man who had collapsed in Taunton on Wednesday afternoon. He later died.
Officers said they were looking at potential links between his death and the use of the psychoactive substance, a spokesman said.
Six other people at the same property in Wheatley Crescent were found ill but did not have to be taken to hospital.
A spokesman said they believed some of those affected may have taken Spice.
Det Insp Liz Hughes said anyone taking similar substances was "playing roulette with your health".
A man may have died after taking the former legal high Spice, police say.