Anaerobic aerotolerant Streptococcus pneumoniae modulates its genetic transformability and its virulence in response to the oxygen concentration. The activity of a single protein encoded by nox and showing NADH oxidase activity is involved in these adaptive responses to O2. Northern blot analysis of wild-type cultures grown under aerobic and microaerobic conditions indicated transcriptional control of comCDE by O2. An O2-independent mutant strain carrying the gain-of-function mutation comE38KE was isolated and its analysis showed that ComE is a key point in competence stimulation by O2. Plasmid insertion mutations in ciaRH revealed that this two component signal-transducing system negatively regulates comCDE transcription. The level of comCDE transcripts appears as a major control point in competence regulation by O2 and also by growth phase and cell density.