Melioidosis is an emerging disease caused by the environmental Gram-negative bacillus Burkholderia pseudomallei. Melioidosis has been reported to be endemic mainly in northern Australia and Southeast Asia. Here, we report the first two cases of melioidosis on the Comorian island of Mayotte. We also describe four cases that occurred over a short period of time in patients who had traveled between Mayotte, Madagascar, and Reunion Island.