Deafness is a medical condition with important relational implications. This condition could affect well-being and self-esteem and cause social anxiety. Sign language is not only a simple mimic but can be considered as a different kind of communication that could be protective for those who have learned it. However, some people do not use sign language because they think it can be marginalizing. The present study aimed to compare the quality of life (QoL) between people who learned Italian sign language as their first language with those who had never learned it or learned it later. This cross-sectional study involved 182 deaf Italian adults (70.3% females) who were recruited from Ente Nazionale Sordi (ENS) and by the main online deafness groups. The present results suggest that the deaf condition does not seem to significantly affect the dimensions of QoL pertaining to satisfaction and self-esteem, while it could have an effect on preventing high levels of social anxiety and in particular, the group who learned Italian sign language showed significantly less social anxiety than those who had never learned it.