Partial results and exit polls should give a clear indication of the outcome soon after.
Last week's first-round vote, while marked by a low turn-out, saw the right-wing UMP win its lowest share of the vote in more than three decades.
Opinion polling is banned in France in the immediate run up to the vote, but in previous regional elections second-round results have closely mirrored first-round tallies.
Sarkozy, whose party still has a comfortable majority in the national parliament, has insisted that the regional poll is not a verdict on central government, but he is expected to order a reshuffle in the next few days.
Meanwhile the Socialist opposition has called on its supporters to turn out in greater numbers to secure their regional strongholds.
Leadership of regional councils in 25 regions - 22 in mainland France and three in overseas territories - is at stake, the Caribbean island of Guadeloupe having already been taken by the Socialists in the first round.