The axoplasmic transport of somatostatin (SS) and substance P (SP) in the cervical vagus nerve was studied in the rat, guinea pig and cat. In preliminary studies, neuropeptide immunoreactivity (IR-SS and IR-SP) was evaluated in extracts of nodose ganglion and vagus nerve using gel and reverse-phase high-performance liquid chromatography (HPLC). In each species, a single immunoreactive form of SP co-eluted with the synthetic undecapeptide on a Bio-Gel P-10 column. More than 95% of transported vagal IR-SS co-eluted with synthetic SS-14. A small percentage in each species co-eluted with SS-28. No larger form, corresponding to a prosomatostatin, was identified in any of the 3 species. On HPLC, IR-SP and IR-SS co-eluted with their synthetic forms. To quantify neuropeptide transport, the vagus nerve was ligated distal to the nodose ganglion. 24 h later in each species, the content of IR-SS and IR-SP was more than 6 times greater in a 3-mm segment of nerve proximal to the ligature than in equal length segments distal to ligature or in the unligated contralateral nerve. In the proximal segment, the net content of IR-SP (pg/3-mm segment, mean ± S.E.M.) was 366 ± 45 in the rat, 2038 ± 184 in the guinea pig, and 912 ± 108 in the cat. The content IR-SS in the same segment was 36 ± 4, 66 ± 13,and575 ± 59pg/3-mm, respectively. The apparent transport velocities were similar for each peptide and among species. The contribution of the nodose ganglion to transported neuropeptide was estimated by crushing the vagus above the nodose ganglion and simultaneously ligating the nerve distal to the ganglion. The percent contribution of the ganglion to transported IR-SS following this procedure was 50% in the rat, 73% in the guinea pig, and 16% in the cat. Nodose ganglion contribution to IR-SP transport was 31%, 50% and 74%, respectively. Estimated turnover of IR-SS and IR-SP within the ganglion ranged from 4.1 to 6.8 times per 24 h in each species. Conclusions from these studies are: (1) by chromatographic criteria, SS-14 and SP-11 are the predominant immunoreactive forms that are transported in the vagus nerve of each species; (2) although differences between species are evident, a sensory origin for a majority of each transported peptide has been confirmed in at least one of the 3 species; (3) in each species, IR-SP exceeds IR-SS transport, in the guinea pig and rat by 10-fold or greater; and (4) similar turnover times within the nodose ganglion and average apparent transport velocities suggest common mechanisms for the peptides' synthesis in and export from the sensory ganglion of origin.