Background: Sexual dysfunction is the most common complication affecting HSCT survivors and is associated with worse psychological distress and patient QOL. Yet, interventions to address sexual dysfunction in HSCT survivors are lacking. Methods: We conducted a single-center randomized clinical trial of a multimodal intervention to address sexual dysfunction in autologous and allogeneic HSCT survivors who were at least 3 months post-HSCT and endorsed sexual dysfunction causing distress. Patients were randomly assigned to the intervention or usual care. Intervention participants met with a trained HSCT clinician for three monthly visits that focused on 1) assessing the causes of their sexual dysfunction; 2) educating and empowering patients to address sexual health concerns; and 3) implementing therapeutic interventions (e.g., vaginal lubrication, medications, intimacy exercises, etc.). We assessed patient global satisfaction with sex, interest in sex, orgasm pleasure, erectile function, vaginal discomfort (PROMIS), QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplant), and psychological distress (Hospital Anxiety and Depression-Scale) at baseline, 3 and 6 months after enrollment. The primary endpoint was to compare patient global satisfaction with sex at 3 months between the study groups. We used linear regression models, adjusting for baseline scores, to evaluate the intervention effects on study outcomes at 3 and 6 months. Results: We enrolled 74.0% (125/169) of eligible patients (mean age = 55.5 (SD=14.0), 67% male). Overall, 93.7% (60/64) of those randomized to the intervention attended all three intervention visits. At 3 months, patients randomized to the intervention reported improved global satisfaction with sex (B=4.7, P<0.001), interest in sex (B=1.3, P<0.001), orgasm pleasure (B=3.3, P<0.001), erectile function (B=10.9, P<0.001), vaginal discomfort (B=-9.6, P=0.008), QOL (B=12.5, P<0.001), anxiety (B=-1.7, P=0.003), and depression symptoms (B=-2.0, P<0.001) compared to those assigned to usual care. The intervention led to sustained effects at 6 months with improvement in global satisfaction with sex (B=5.2, P< 0.001), interest in sex (B=0.9, P = 0.009), orgasm pleasure (B=3.6, P<0.001), erectile function (B=12.7, P<0.001), vaginal discomfort (B=-13.5, P<0.001), as well as QOL (B=9.2, P=0.002), anxiety (B=-2.0, P=0.001), and depression symptoms (B=-1.4, P=0.006). Conclusions: A multimodal intervention delivered by trained HSCT clinicians results in sustained improvements in sexual health outcomes, QOL, and psychological distress among HSCT survivors. A future multi-site trial is needed to demonstrate the generalizability of these findings across care settings in diverse HSCT survivors. Clinical trial information: NCT03803696.