Bullying has been traditionally related to a significant reduction in well-being and Health-Related Quality of Life (HRQoL) of adolescents. This negative impact on HRQoL seems to be modulated by the developed role in bullying (uninvolved, bully, victim or bully-victim). However, no studies have identified if these negative results are the same when other types of bullying, such as homophobic bullying, are evaluated. The main aim of the present study was to analyze the prevalence of different roles of bullying and homophobic bullying and the relationship between these roles in both types of bullying with HRQoL, depression and anxiety levels in a sample of 1723 Spanish adolescents. Although results exhibited lower prevalence of homophobic bullying roles when compared to traditionally bullying in general, in the case of victims, the prevalence was high in the case of homophobic bullying. When differences between roles in HRQoL, depression and anxiety were evaluated, in both types of bullying, uninvolved adolescents showed the best results and bully-victim adolescents the worst. The obtained results suppose an improvement in the understanding of the negative effects of different types of bullying on HRQoL and mental health in adolescents. Future research could advance in this comprehension, analyzing possible differences with other types of bullying, such as cyberbullying.