Being able to defend victims of school bullying is central in any intervention; thus, it seems paramount to investigate which factors may contribute to defending behavior. The present report aims to investigate whether empathic self-efficacy is associated with helping behavior and whether interpersonal factors (i.e., social preference and student-teacher relationship) may interact with it. The sample comprised 249 middle-school students (47.80% boys) aged 11-14 years, who received peer nominations on defending behavior and social preference. Self-reports were used to assess empathic self-efficacy and the relationship with the teachers. Results highlight a positive association between empathic self-efficacy and defending behavior when social preference and a positive relationship with teachers were average or high but not when they were low. Results are discussed in light of the importance of considering individual and interpersonal factors to understand defending in bullying situations and to develop intervention programs.