Human rhinovirus (HRV) infection can be inhibited in vitro by antibody directed against the cellular receptor for the major HRV group representing 90% of serotypes. We assessed the prophylactic effectiveness and safety of intranasally administered rhinovirus receptor murine monoclonal antibody (RRMA) in two double-blind, place-controlled, randomized studies of volunteers experimentally inoculated with HRV-39. In the first study, RRMA administration (135 micrograms/subject in 9 applications, -17 to +48 h) did not reduce infection (RRMA 12/15 vs. placebo 13/15) or illness (8/12 vs. 7/13) rates or modify the clinical course of experimental HRV-39 colds. In the second trial, a higher RRMA dosage (1 mg/subject in 10 applications, -3 to +36 h), similarly did not reduce overall infection (11/13 vs. 12/13) or illness (7/11 vs. 9/12) rates, but was associated with a 1-2 day delay in the onset of viral shedding and cold symptoms and with significant reductions in viral titers and nasal symptoms on the second day after challenge and in mucus weights on the third day after challenge. No toxicity related to RRMA was recognized. The results indicate that intranasal RRMA modified infection and illness after experimental HRV-39 challenge and suggest that blockade of host cell receptors offers a novel antiviral approach against HRV infections.