Officers were called to Montpelier Place, Brighton, at 10.15pm on Wednesday (4 November) following reports of a fight involving around 20 people.
A 40-year-old man suffered stab injuries and was taken to Royal Sussex County Hospital for treatment, where he remains in a serious condition.
Two men – aged 19 and 57 – were swiftly arrested nearby and remain in custody at this time.
Two further men – both 18 – were arrested in connection with the investigation on Thursday (5 November) and remain in custody for questioning.
Detective Chief Inspector Gordon Denslow, from the Sussex Police Major Crime Team, said: “Our investigation is moving at pace as we work quickly to establish what happened.
“This incident happened in a busy area of Brighton and we are appealing to anyone who witnessed the assault, or may have relevant CCTV/dash-cam footage or was in the Montpelier Place area at the time of the assault to come forward.
“We are confident that someone knows what happened and would urge them to do the right thing and speak to us immediately.
“The victim and suspects are believed to be known to each other and this is being treated as an isolated incident with no threat to the wider public.
“This is a complex investigation and we thank the public for their patience as enquiries are ongoing and an increased police presence remains in the area.”
You can report information either online or call 101 quoting Operation Moorcroft.
Alternatively you can contact the independent charity CrimeStoppers anonymously on 0800 555 111.