Background: Caregivers of patients with primary malignant brain tumors (PMBT) face unique challenges caring for someone with a progressive neurological illness. In preliminary studies, we found that 50% or more of caregivers had clinically significant anxiety symptoms in the months following the patient’s PMBT diagnosis. However, few interventions have been developed to specifically target anxiety symptoms in this population. Methods: We conducted a randomized controlled trial evaluating the efficacy of NeuroCARE, a population-specific intervention addressing anxiety in caregivers of patients receiving treatment at two academic centers. Eligible caregivers were within six months of the patient’s PMBT diagnosis and had clinically significant anxiety symptoms (score ≥ 5 on the Generalized Anxiety Disorder-7 tool). Participants were randomized 1:1 to NeuroCARE or usual care. NeuroCARE consisted of six one-on-one telehealth sessions with a mental health clinician or trainee and incorporated evidence-based skills for 1) coping with worry, 2) using assertive communication techniques, 3) optimizing social support, and 4) promoting relaxation and healthy sleep. Participants completed questionnaires at baseline, 11 weeks (immediately post-intervention) and 16 weeks (1 month post-intervention). Our primary endpoint was anxiety symptoms at 11 weeks (Hospital Anxiety and Depression Scale (HADS) – Anxiety Subscale score). We also assessed depression symptoms (HADS – Depression Subscale), quality of life (QOL; Caregiver QOL survey), caregiver burden (Caregiver Reaction Assessment), self-efficacy (Lewis Cancer Self-Efficacy scale), coping (Measure of Current Status) and post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist for DSM-5). We used analysis of covariance to evaluate the effect of NeuroCARE versus usual care on these outcomes. Results: We enrolled 120 caregivers (60 per arm, mean age = 53 years, 83% female), the majority of whom were caring for their spouse/long-term partner (70%), child (17%), or parent (7%). At 11 weeks, NeuroCARE participants reported significantly lower anxiety symptoms than those assigned to usual care (means: 8.87 vs 10.69, p = 0.008). NeuroCARE caregivers also reported significantly lower depression symptoms (6.08 vs 7.77, p = 0.004) and better self-efficacy (128.81 vs 111.17, p < 0.001) and coping (32.25 vs 25.65, p < 0.001) at 11 weeks. Study groups did not differ with respect to caregiver burden, PTSD symptoms, or QOL at 11 weeks. Conclusions: A population-specific telehealth-based psychological intervention (NeuroCARE) led to significantly lower anxiety and depression symptoms and better self-efficacy and coping among caregivers of patients with PMBT compared with usual supportive care. Clinical trial information: NCT04109209.