Intranasal monoclonal antibodies (mAbs) offer a promising cost-reducing and non-invasive alternative to systemic administration. Intranasal palivizumab prevented respiratory syncytial virus (RSV) infection in mice but not in healthy infants. This proof-of-concept study evaluates the efficacy of intranasal palivizumab to prevent RSV infection. In this randomized, double-blind, placebo-controlled, experimental infection model, 28 healthy adults (18–55 years old) were randomized 1:1 to receive 1 mg/mL palivizumab in saline nasal drops or placebo one hour prior to RSV-A Memphis 37b challenge (EU clinical trial register 2020-004137-21, August 14, 2021). The primary outcome was viral load over time, determined by RT-qPCR. Intranasal palivizumab had no effect on viral load despite a 72% reduction in symptomatic infections and marginally reduced upper respiratory tract symptoms compared to placebo. Intranasal palivizumab does not protect against RSV infection under optimally controlled conditions. Intranasal mAbs are highly unlikely to be a feasible and cost-effective method of protection against respiratory infection.