The fighting, expected before winter sets in, could deeply involve Hezbollah, key ally of Syrian President Bashar Assad, which has vital strongholds and supply lines along the rugged frontier, particularly the Bekaa Valley, the Shiite movement's heartland.
The region, about 15 miles wide and 50 miles long, extends from rural Damascus to Lebanon's mountainous border where peaks rise to 4,500 feet.
Most of the villages, and the key town of Arsal, are held by rebels and their Lebanese allies.
By some accounts, there are 25,000 rebels, including jihadists, deployed there. Hezbollah, which has thousands of rockets, is reported to have beefed up its forces in the region, too.
The rebels have been sparring with Hezbollah for months in Qalamoun. If Hezbollah becomes heavily embroiled in the expected battle, which could involve fighting on Lebanese soil, it could trigger internal clashes with Sunni groups in Lebanon.
The various rebel groups, who seem to spend as much time fighting each other as Assad's army, are digging in around village strongholds.
"We know it's coming soon," said one veteran Sunni fighter.
The risk of the fighting spilling over across Lebanon, which has been steadily dividing into pro- and anti-Assad camps along sectarian lines for some time, already is considered high.
Rebel Sunni jihadists opposed to the Shiite Hezbollah have planted bombs in the group's stronghold in southern Beirut. There are reports four cars packed with explosives have been infiltrated into Lebanon from Syria to attack Hezbollah neighborhoods.
"Both sides believe this showdown is inevitable because the region is a vital artery that feeds fighters and weapons to the Syrian hinterland," says Lebanese analyst Radwan Mortada.
A key target is the Joussieh border crossing held by the Syrian army and Hezbollah, which the largely Sunni rebels have twice tried, and failed, to seize.
Saudi Arabia, Assad's most powerful Arab enemy, seems to be spoiling for a fight and knowledgeable Arab sources see prospects of inflicting a decisive defeat on regimes forces in Qalamoun.
The Saudis, exasperated with the United States for backing off threatened airstrikes against the Syrian regime last month after its Aug. 21 poison gas attack against a rebel-held sector of Damascus, are reported to be funneling arms and funds to the rebels in the Qalamoun region.
Another primary target for the regime is Mount Snir, a long north-south ridge that runs parallel to the important highway between Damascus and the western city of Homs that runs in the valley below its eastern flank.
One of the main rebel units in the region is Liwa al-Islam -- the Brigade of Islam -- a highly effective Saudi-sponsored group commanded by Zahran Alloush, son of a prominent Saudi religious scholar.
This well-organized group, which seems adept at coordinated attacks, has made major advances in the region in recent weeks, including driving Assad's 81st Brigade out of the town of Ruhaiba Sept. 1.
Alloush, who reputedly has 3,000-5,000 men, was reported to have recently met Prince Bandar bin Sultan, director of Saudi Arab's General Intelligence Directorate and a diehard opponent of the Syrian regime which is backed by Iran, Riyadh's principal adversary in the region.
The Assad regime, whose military campaign Arab sources say is largely controlled by the elite Al-Quds Force of Iran's Revolutionary Guard Corps, appears to be poised to unleash a major offensive against the rebel-held Qalamoun region.
Military analysts say the regime may attack soon to prevent the disparate rebel forces establishing a united front that could threaten the northern Bekaa and the key highway between Damascus and Homs.
But the weather's likely to be the deciding factor, since winter rains and snow make movement extremely difficult in the mountains.
The regime hopes to exploit the rifts within the rebel movement, particularly between hard-line jihadists of the Islamic State of Iraq and al-Shams and more secular Western-backed Free Syrian Army.