Objectives: We describe the preliminary results of bulevirtide compassionate use in patients with hepatitis B and delta virus (HBV/HDV)‐related cirrhosis and clinically significant portal hypertension, including those living with HIV. Methods: We conducted a prospective observational study of consecutive patients. Clinical evaluation, liver function tests, bile acid levels, HDV‐RNA, HBV‐DNA, hepatitis B surface antigen, and liver and spleen stiffness were assessed at baseline and after treatment months 1, 2, 3, 4, 6, 9, and 12. HIV‐RNA and CD4+/CD8+ count were assessed in people living with HIV. The first drug injection was administered under nurse supervision, and counselling was provided and adherence reviewed at each visit. Results: In total, 13 patients (61.5% migrants) were enrolled. The median treatment duration was 11 months. At month 6, mean alanine aminotransferase (ALT) levels fell by 64.5% and mean liver and spleen stiffness decreased by 8.6 and 0.9 kPa, respectively. The mean baseline HDV‐RNA was 3.34 log IU/mL and 5.10 log IU/mL in people without and with HIV (n = 5) (p = 0.28), respectively. A similar mean decline was observed in both groups: −2.06 log IU/mL and −1.93 log IU/mL, respectively (p = 0.87). A combined response (undetectable HDV RNA or ≥ −2 log IU/mL decline vs. baseline, with ALT normalization) was achieved in 66% of subjects without and in 60% of patients with HIV. Patients with HIV showed persistently undetectable HIV‐RNA and a progressive increase in CD4+/CD8+ cells during treatment. No patient discontinued bulevirtide because of adverse effects. Conclusions: Preliminary results suggest that bulevirtide is feasible and well‐tolerated in populations with difficult‐to‐treat conditions, such as those with HIV/HBV/HDV co‐infection and migrants, when special attention is given to patient education. HDV‐RNA decline during treatment was similar in people living with and without HIV. [ABSTRACT FROM AUTHOR]