The first phase of the qualifiers involves the six least ranked teams on the continent, which will see the three winners joining the 45 others for the group phase.
On Wednesday, Sao Tome and Principe launches their campaign against Madagascar in Sao Tome in a battle of islanders, with the latter in search of a win to boost their chances of making the group stage.
Unlike Sao Tome, Madagascar bowed out of the last qualifying campaign with three draws including a famous 1-1 draw against Angola away in Luanda last September, a result which gives them confidence ahead of the trip to Sao Tome.
Still on Wednesday, Djibouti will be at home to South Sudan in Djibouti whilst Comoros squares Mauritius in Mitsamiouli on Thursday.
The return legs will take place between 26 and 28 March 2017.
22.03.2017 Sao Tome Sao Tome vs Madagascar
22.03.2017 Djibouti Djibouti vs South Sudan
24.03.2017 Mitsamiouli Comoros vs Mauritius