NSW Premier Gladys Berejiklian has vowed to stop Sydney music festival Defqon.1 after two young people died and another two were left fighting for their lives after multiple suspected overdoses.

Around 700 people were treated, including 18 who were hospitalised, during the event at Castlereagh in southwestern Sydney on Saturday.

"I'm absolutely aghast at what's occurred. I don't want any family to go through the tragedy that some families are waking up to this morning," she said.

"This is an unsafe event and I'll be doing everything I can to make sure it never happens again.

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"I never want to see this event held in Sydney or NSW ever again... Young lives were lost for no reason."

A man, 23, and a woman, 21, collapsed at the festival about 9pm on Saturday and died a short time later in nearby Nepean hospital, police said on Sunday.

A Jamisontown woman, 26, remains in a critical condition at Nepean hospital while an Artarmon man, 19, was flown to Westmead Hospital and is in intensive care.

Police said another 18 people went to hospital for drug-related issues while about 700 people sought assistance from medical staff at the festival.

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Defqon.1 organisers had warned ticket holders the festival's drug policy was zero tolerance.

"This means that all types of soft- and hard drugs are prohibited. If drugs are found, you will be handed over to the police," a statement on the festival's website said.

Police say 10 people were charged with drug supply offences, including two 17-year-old girls who allegedly carried 120 capsules "internally" into the venue.

In total, 69 people were found in possession of drugs at the festival held at Sydney International Regatta Centre.

Local detectives have formed a new police strikeforce, dubbed Highworth, to investigate the two deaths.