Axons immunoreactive for calcitonin gene-related peptide (CGRP) and substance P are present in the olfactory nerve, although few, if any, olfactory receptor cells contain immunocytochemically detectable levels of these peptides. The possible trigeminal origin of these fibers was tested by performing unilateral stereotaxic lesions of the ophthalmic division of the trigeminal nerve, followed 2-25 days later by immunocytochemistry for CGRP and substance P. As reported previously, free nerve endings immunoreactive for both peptides were found transversing the nasal epithelium on the unlesioned side. Also on the unlesioned side, peptidergic axons, immunoreactive for both CGRP and substance P, could be traced from the olfactory nerve into the glomerular layer throughout the olfactory bulb, but especially into its rostral third. Ipsilateral to the trigeminal ganglion lesion, such peptide-immunoreactive fibers were absent or markedly reduced in the bulb, nerve, and epithelium. These results indicate that the peripheral branches of the ophthalmic branch of the trigeminal nerve enter the olfactory bulb along with the olfactory nerve and terminate in the glomerular layer along with the olfactory axons. Ultrastructural analysis of the CGRP-immunoreactive terminals in the glomeruli reveal vesicle-filled axonal processes terminating in the absence of obvious pre- or postsynaptic specializations. Whether the trigeminal fibers in the bulb are functional, e.g., convey information to the olfactory bulb via an axon reflex, or relay information from the olfactory bulb to the brainstem trigeminal nuclei is unclear.