Background Persistent post-mastectomy pain (PPMP) varies both in its severity and impact, with psychosocial factors such as catastrophizing conferring greater risk. Preoperative regional anesthesia (RA) is an important nonopioid therapy, but with variable success at preventing PPMP in previous reports. We previously reported that RA was associated with lower acute post-mastectomy pain and opioid use, but more prominently among patients with higher baseline catastrophizing. The current longitudinal investigation at 3, 6, and 12 months postop aimed to detect differential long-term impact of RA on PPMP among patients with high vs low catastrophizing. Methods In this prospective observational study, patients (n = 123) completed preoperative psychosocial assessment and underwent mastectomy either with (n = 56) or without (n = 67) preoperative RA. Generalized estimating equation (GEE) regression analysis assessed impact of baseline catastrophizing, RA, and their interaction, on the primary outcome of pain severity index, as well as secondary outcomes including cognitive and emotional impact of pain, and persistent opioid use. Results We observed a significant interaction between the effect of catastrophizing and RA on PPMP. Specifically, RA was associated with reduced pain severity and pain impact 3, 6, and 12 months postoperatively, but only among those with high baseline catastrophizing scores. In addition, both RA and lower catastrophizing scores were associated with lower incidence of persistent opioid use. Conclusions The efficacy of therapies to prevent PPMP may be importantly influenced by pain-modulatory psychosocial characteristics. These findings underscore the importance of considering individual patient factors when applying preventive treatments, and of including their assessment in future trials. [ABSTRACT FROM AUTHOR]