France were rewarded for a sustained spell of late pressure as they triumphed 10-9 against an Ireland side who were left counting the cost of more injuries.
Jonathan Sexton's boot had kicked Ireland into a 9-3 lead in a scrappy, error-strewn encounter at a wet and windy Stade de France on Saturday.
But France, who had struggled for possession in the opening hour in Paris, bombarded the Irish try line and Guy Noves made it two from two as France head coach when Maxime Medard scored the only try in the 69th minute.
For Ireland – who drew 16-16 versus Wales last weekend – the defeat was made worse by a quartet of injuries to Sean O'Brien, Dave Kearney, Mike McCarthy and Sexton.
With the likes of Simon Zebo, Keith Earls, Tommy Bowe and Luke Fitzgerald already sidelined, the defending champions now face an uphill battle to retain the title.
Ireland were camped in France territory for the opening 15 minutes and Sexton put the visitors on the scoreboard with the boot after taking a late hit from Yoann Maestri that may result in a call from the citing commissioner.
O'Brien, back in Ireland's XV after a hamstring problem, limped off with another apparent leg injury, before France's indiscipline led to a penalty on the left flank that Sexton converted.
A Jules Plisson penalty put the hosts on the board, but the physical nature of the match took its toll on Ireland, who lost Kearney to a shoulder injury, while McCarthy went into the blood bin after taking a blow to the face.
Sexton split the posts for a third time to stretch Ireland's lead before Plisson missed with a kick of his own on the stroke of half-time.
There were few opportunities at the start of the second period, but France started to turn the screw and Andrew Trimble made a crucial interception from Plisson's pass when the hosts had the overlap.
McCarthy was taken from the field on a stretcher with a head injury following that play, before Ireland defended for their lives at the line – Damien Chouly went over the whitewash, but referee Jaco Peyper ruled the ball was held up.
It was then a double Ireland blow as the influential Sexton went off after receiving treatment to his neck, before France got the winning try.
After a series of driven scrums, France got quick ball and Medard's clever line saw him touch down under the posts to leave a simple conversion as the home side followed up last weekend's 23-21 win over Italy in dramatic fashion.