It's believed at least 140 people were killed and more than 200 wounded in the previously quiet heartland of President Bashar al-Assad's Alawite minority.
Civilians in the government-held towns of Tartous and Jableh were targeted in attacks by at least five suicide bombers and two devices planted in cars.
They were towns that had up until now escaped the worst of the violence in the five year-old conflict.
Government ally Russia maintains a naval facility in Tartous, and Jableh in Latakia province is near a Russian-operated air base.
IS say it was targeting members of President Bashar al-Assad's Alawite minority, and issued another statement explaining why those cities were targeted.
"So they experience the same taste of death which Muslims so far have tasted from Russian and Syrian government air strikes on Muslim towns."
European Union Foreign Policy Chief Federica Mogherini says the violence in Syria strengthens the EU's resolve.
"What we have seen today in terms of killing of civilians is completely unacceptable and makes our determination to make the cessation of hostilities work even stronger, and our determination to work for the humanitarian access to all besieged areas even stronger."
For many of those in Tartous, the scene was just too much.
Local man Mahmoud Hasan says he just doesn't understand it.
"People were running away, this was at 10am, the time students were leaving for school. The fourth explosion took place near the Abu Nadim supermarket. Four explosions. Many people were killed and many were injured. This is incomprehensible."
Footage of the scenes show large-scale damage, including several twisted and burnt-out cars and minivans.
One of the four blasts in Jableh hit near a hospital, as eyewitness Bassen Al-Hassan explains.
"We went to help the injured. Once we got closer to the car, an explosion took place inside the hospital. When the explosion took place we returned back for five minutes. A girl exploded herself in the emergency department in the hospital. When we knew that we went back to help the injured and the martyrs and we started to move them in ambulances to private hospitals."
Russia's parliament says the bomb blasts underscore the need to press ahead with Geneva peace talks.
It says Russia's President, Vladimir Putin, has reiterated his readiness to fight with the Syrian government against what he calls "the terrorist threat."
He has also sent his condolences to Syria's President.
The war in Syria has killed at least 250,000 people so far.
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