Spain spurred on by USA defeat
Boosted by Saturday's 5-0 win over Belgium, Spain will make sure of their place in South Africa if they beat the rank outsiders in Merida and second-placed Bosnia drop points at home to Turkey the same evening.
Spain have a 100 percent record in their seven games in European Group Five and even if Bosnia win on Wednesday, it would take an unlikely combination of results to deprive Vicente del Bosque's team of top spot.
The winners of the nine European groups qualify for South Africa while the eight best runners-up play off among themselves for four more places.
"We have to keep on pushing because we still need four points to seal our qualification mathematically, and we can't take anything for granted until we have them," Del Bosque said.
Estonia are fifth with only one win from seven qualifiers, and have the leakiest defence with 19 goals against. They lost 4-2 in Turkey on Saturday but are not expected to make major changes to their side.
Saturday's win in La Coruna was a welcome tonic for Spain after they were knocked out of the Confederations Cup by the United States in June.
"Being knocked out of the Confederations Cup forced us to have a rethink because we had been a little inconsistent," said Del Bosque.
"We had to work hard to beat Belgium. The first half was tough but we read the game well. It was good for us to get a win like this."
Against Belgium, there was little evidence of complacency or of the vulnerability to swift breaks that bedevilled their defeat by the U.S. and their 3-2 comeback win over Macedonia in a friendly last month.
Brazilian-born midfielder Marcos Senna was not risked, having just returned from injury, but could be recalled against Estonia, although David Silva appears assured of another start after his two goals on Saturday.
Spain: Iker Casillas; Alvaro Arbeloa, Gerard Pique, Carles Puyol, Joan Capdevila; Xavi, Marcos Senna, Xabi Alonso, David Silva; Fernando Torres, David Villa
Estonia: Sergei Pareiko; Ragnar Klavan, Raio Piiroja, Alo Barengrub, Anar Jaager; Dmitri Kruglov, Konstantin Vassiljev, Aleksandr Dmitrijev, Joel Lindpere; Vladimir Voskoboinikov, Andres Oper.