Pseudomonas aeruginosa colonizes the respiratory tract of Cystic Fibrosis patients, where a high proportion of mutators along with mucoid, alginate-overproducing variants, emerge leading to chronic infection and a poor prognosis for the patient. Mucoid conversion generally involves mutations inactivating the mucA gene. Irrespective of the kind of mutation carried by the mucA gene, the mucoid phenotype is typically unstable under standard laboratory conditions. The genetic changes responsible for the conversion to a non-mucoid phenotype are apparently not produced by direct reversions of the original mutation in mucA, but through second site mutations suppressing the expression of the alginate biosynthetic pathway. This study correlates the activity of factors determining the mutation rate, such as MutS and DNA polymerase IV (Pol IV), with the emergence of mucoid variants as well as the instability of this phenotype. MutS is a main component of the Mismatch Repair System involved in the correction of errors produced in replication. Pol IV is an error-prone DNA polymerase involved in “stress-induced mutagenesis”, member of the Y family of DNA polymerases encoded by the dinB gene. Results show that: (i) the emergence frequency of mucoid variants was higher in isolates arising from mutS populations compared with the wild-type strain; (ii) however, mucoidy was highly unstable in the mutator strain; (iii) in both strains mucoid conversion occurred mainly by mutations in the mucA gene; (iv) but in any case the reversion process occurred via correction of the mucA mutation; (v) disruption of dinB in the wild-type and mutS strains decreased drastically the emergence frequency of mucoid variants; (v) As well, disruption of dinB in mucoid variants derived from the wild-type and mutS strains contributed to stability of the mucoid phenotype by decreasing the reversion frequency to a non-mucoid state. Taken together results demonstrate antagonistic effects between MutS and Pol IV in the generation of mucoid variants as well as in the maintenance of mucoidy. At present efforts are being made pursuing the mechanistic bases of the reversion process.