Those arrested are thought to be connected with spate of tit-for-tat shootings of gangland figures in Salford.
Dawn raids on Tuesday led to the arrest of three Salford men in their twenties on suspicion of conspiracy to commit murder, possession of a firearm and membership of an organised crime group.
The youngest of the men - aged 20 -was also wanted on a European Arrest Warrant by Greater Manchester Police for possession of class A drugs and counterfeit currency.
A 41-year-old man from Trafford and a 31-year-old woman from Dublin, Ireland were also arrested on suspicion of membership of an organised crime group.
Two properties were raided as part of the operation where officers recovered a loaded hand gun and ammunition and four knives.
Earlier this month another Salford man connected with the gang was arrested in Marbella on a European Arrest Warrant on suspicion of possession of class A drugs with intent to supply.
The operation, led by Spanish National Police with support from Greater Manchester Police and the National Crime Agency, was part of an investigation into a war between rival drug gangs that saw Salford's so called Mr Big, Paul Massey, shot dead at his home last July.
Assistant Chief Constable Rebekah Sutcliffe from Greater Manchester Police said: "These arrests are a significant result for Greater Manchester Police in our fight against organised crime in Salford. This sends out a clear message to all those involved in organised crime, that we will never give up and we will find you, even if you have left the country.
"We would like to thank the Spanish National Police and the National Crime Agency, once again they have shown their determination to relentlessly pursue criminals and fugitives who seek to use Spain as a base for their criminal activities.
"Our commitment to tackling serious organised crime in Salford will continue and we will use all of the powers and information available to us and our partners to target this criminality round-the-clock and put a stop to it for good.
Dave Allen, Head of the International Crime Bureau at the National Crime Agency said: "Law enforcement does its best work and has the most impact when it pools resources and works collaboratively.
"This is an excellent result, which shows the determination and professionalism of the Spanish National Police, the National Crime Agency and UK police forces, in targeting organised crime groups and fugitives who seek to use Spain as a base for their criminal activities."