Police on both sides of the border have run large scale operations to drug and alcohol test drivers leaving Strawberry Fields.
Dozens of police manned roadblocks at Tocumwal and Koonoomoo as people began leaving the annual event.
Officers have caught more than 200 people drug driving, or in possession of drugs, during operations in previous years.
Wangaratta Senior Sergeant Darren Wittingslow said police wanted to see people arrive home safely from the festival.
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"This is to ensure that drivers of the vehicles are drug and alcohol free," he said.
"The primary reason we undertake roadblocks and patrols is to ensure the safety of all road users from the effects of those people who decide to take the risk and drive impaired.
"We have a very strong response as patrons leave the musical festival.
"This is to ensure the safety of all road users in Victoria as people travel."
Officers had undertaken hundreds of tests and earlier searched vehicles heading to the event.
NSW Superintendent Jason Weinstein said taking drugs was like "loading a gun into a bullet and then firing that bullet".
"Does drug taking still occur at festivals?" he said.
"Yes it does.
"We make it known that we conduct operations to attempt to deter drugs from entering and those who intend on supplying those evil and disruptive items, that's the reason why we're there."
Attendees have in previous years been found with large amounts of drugs including Kevin Clough, who was caught with 14.2 grams of ecstasy last year.
Magistrate Rodney Brender recently told Clough drug dealing was a serious offence given there have been deaths.