Purpose <p>Rabies is a fatal zoonotic disease, and India accounts for 35% of global rabies-related deaths. In 2018, the World Health Organization (WHO) revised its guidelines for pre-exposure prophylaxis (PrEP) from a 3-dose to a cost-saving 2-dose intradermal (ID) regimen. This study evaluates the immunogenicity and safety of this regimen in pediatric populations, including children exposed to immunosuppressant therapy.</p> Methods <p>This single-center, prospective, comparative follow-up study was conducted at a tertiary care hospital. Participants (5–18 years) were enrolled into two groups: (1) children with no known immunodeficiency (<i>n</i> = 31) and (2) children on immunosuppressant therapy (<i>n</i> = 10). All received Vero cell culture rabies vaccine (RABIVAX-S^®) intradermally at two sites on days 0 and 7. Serum anti-rabies virus glycoprotein antibody titres were assessed on days 28, 90, and 180 using an ELISA-based assay. Booster doses were administered to those with insufficient titers (≤ 0.5 EU/ml).</p> Results <p>By day 28, both groups achieved a 100% seroconversion rate (SCR). Geometric mean titers (GMT) were 2.168 EU/ml and 1.547 EU/ml in the no-known-immunodeficiency and immunosuppressant therapy groups, respectively. At day 90, SCRs were 90% and 70%, with GMTs of 1.358 EU/ml and 0.962 EU/ml, respectively. Booster doses restored titers in all participants with insufficient levels. Pain at the injection site was the only solicited adverse effect.</p> Conclusions <p>The 2-dose ID PrEP regimen is immunogenic and safe in pediatric populations, including immunosuppressed children. It offers a cost-effective alternative in rabies-endemic regions, enhancing compliance and accessibility.</p> Trial registration <p>Prospectively registered with the Clinical Trials Registry India with Trial Registration No. CTRI/2022/10/046777.</p>