Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa. [Display omitted] • Perineurial olfactory nerve fibroblasts enwrap and protect olfactory axon fascicles • Virions make it in some cases to the leptomeninges covering the olfactory bulb • Absence of evidence for neurotropism and neuroinvasion of several SARS-CoV-2 variants Khan et al. visualized infected cells, ongoing viral replication, and extracellular virions in postmortem tissue samples of COVID-19 patients who died during an acute phase of infection. They identified anatomical barriers protecting against SARS-CoV-2 neuroinvasion at vulnerable interfaces along the olfactory projection and in the frontal lobe of the brain. [ABSTRACT FROM AUTHOR]