Ventilator-associated pneumonia (VAP) develops in approximately 20% of patients in the ICU receiving prolonged mechanical ventilation (MV). Among the range of methods for preventing VAP, the evidence base for topical antibiotics (TAs), including selective digestive decontamination, appears to be the most compelling. However, several observations are puzzling, and the contextual influence resulting from concurrent use of both topical placebo and TA within an ICU remains untested. As with herd protection conferred by vaccination, contextual influences resulting from a population-based intervention cannot be estimated at the level of a single trial. Estimating contextual effects requires multilevel random-effects methods. In this way the dispersion in VAP incidence across groups from 206 studies, as cited in various-source systematic reviews, was calibrated. The benchmark mean VAP incidence derived from 49 observational groups of patients receiving MV is 23.7% (95% CI, 20.6%-27.2%). In contrast, for 20 and 15 concurrent control groups from the TA evidence base that did vs did not receive topical placebo, respectively, this incidence is 38% (95% CI, 29%-48%) and 33% (95% CI, 20%-50%). This contextual influence remains significant in a meta-regression model adjusted for group-level variables, such as within a trauma ICU context. The mean VAP incidence for five other categories of control groups from the broader evidence base is within four percentage points of the benchmark. The contextual effect of TA is paradoxic, peculiar, potent, perfidious, and potentially perilous. The TA evidence base requires reappraisal to consider this herd peril.