Human rhinoviruses (HRVs) are quite sensitive to low pH. To determine whether this characteristic might be a therapeutic target, we evaluated the sensitivity of HRV to low-pH buffers in vitro and in vivo. Our findings confirm that low pH inhibited replication of most HRVs and reduced the replication of influenza virus. Preliminary experiments verified that the surface pH of the human nasopharynx could be transiently lowered to pH approximately 4.0 by topical administration of citrate/phosphate (CP) buffers, which was well tolerated. In a pilot experimental colds study, intranasal administration of CP buffer, compared with normal saline, reduced viral shedding by 1 log unit (10(3) vs. 10(4) 50% tissue culture infective dose/mL; P<.01), although respiratory symptoms were not significantly reduced. These findings demonstrate that low-pH buffers have antiviral activity in vivo and suggest that a larger clinical trial is warranted to determine whether this approach could reduce rates of viral transmission.