Emergency services initially said the man and woman had symptoms “consistent with Novichok poisoning” but this was later ruled out as the cause.
Wiltshire Police said a man aged in his 40s and a woman aged in her 30s had become unwell in Prezzo, in High Street, at around 6.45pm on Sunday.
“Due to recent events in the city and concerns that the pair had been exposed to an unknown substance, a highly precautionary approach was taken by all emergency services,” the force said.
“Both were taken to Salisbury District Hospital and were clinically assessed. We can now confirm that there is nothing to suggest that Novichok is the substance. Both people remain in hospital under observation.
“The major incident status has now been stood down.”
A source briefed by the emergency services said medics alerted the police because the symptoms were consistent with Novichok poisoning, but stressed the symptoms could be caused by other reasons.
“The ambulance crew at the site took the decision that the symptoms seemed consistent with Novichok poisoning which is why they called their colleagues in the police,” the source said.
But the source stressed: “The symptoms of Novhichok poisoning and particular types of narcotic abuse are very similar.”
One witness who was in Prezzo told the BBC those taken ill were “two Russians”, and the woman became distressed after repeatedly getting up from her table and returning.
“When she came back she was hysterical. She called paramedics and the next thing an ambulance turns up and they come rushing in,” the unnamed witness said.
Police, ambulance and fire services attended the scene with some donning hazmat suits.
Salisbury resident, Sam Proudfoot, 16, told HuffPost UK: “The street is all cordoned off and there’s two fire engines, half a dozen police cars, two incident response units, and an ambulance.
“There’s a man in a full white body suit with a mask to his mouth going in and out of the back of the ambulance and the restaurant and the area’s been cordoned off for about 50 metres in all directions.”
A witness in the nearby Cafe Rouge restaurant said they could see police bagging something up in the street outside.
Tensions are heightened in the cathedral city because of recent Novichok poisonings.
The Italian restaurant is a short walk from Queen Elizabeth Gardens, which was until recently closed off after 44-year-old Dawn Sturgess was fatally poisoned by the nerve agent.
Police said she was killed by the same chemical used in an alleged hit by Russian military intelligence officers on former spy Sergei Skripal.
Public Health England said they had been made aware of the incident.
Salisbury City Council leader Matthew Dean tweeted: “Understandably people concerned at latest possible incident in Salisbury but there have been a number of false alarms since the Skripal poisoning.
“Rightly the emergency services start with a highly precautionary approach until they know otherwise.”