BACKGROUND: Hypercobalaminemia is infrequently reported in companion animals and is considered of low clinical significance. Recent studies have described its association with inflammatory, immune-mediated, endocrine, and neoplastic conditions in dogs and cats. OBJECTIVES: We aimed to investigate the association between hypercobalaminemia and neoplasia in companion animals and to identify other concurrent diseases or clinicopathologic changes. METHODS: This is a retrospective, case-control study. Medical records of patients with measured serum cobalamin concentration (2015-2020) and no history of prior supplementation were reviewed. Hypocobalaminemic animals were excluded. Variables were compared between groups (hypercobalaminemic vs. normocobalaminemic) using non-parametric statistics. Data are presented as median (range). RESULTS: Thirty-five dogs and eight cats were hypercobalaminemic. At baseline, neoplasia was confirmed in 4/35 hypercobalaminemic dogs versus 11/70 control dogs (P = 0.77) and 0/8 hypercobalaminemic cats versus 3/16 control cats (P = 0.53). Cases without neoplasia at baseline were followed for 409 (13-1854) days (dogs, n = 78) and 395 (28-1670) days (cats, n = 21). During follow-up, neoplasia was diagnosed in 4/27 hypercobalaminemic dogs versus 3/51 control dogs (P = 0.23) and 1/8 hypercobalaminemic cats versus 0/13 control cats (P = 0.38). Pancreatitis was more frequent in hypercobalaminemic dogs (P = 0.006). Hypercobalaminemic dogs had higher serum total protein (P = 0.014), globulin (P = 0.001), and CRP (P = 0.032) concentrations and lower serum sodium (P = 0.012) and chloride (P = 0.033) concentrations than controls. Hypercobalaminemic cats had higher serum total protein concentrations than controls (P = 0.008). CONCLUSION: Our results suggest that hypercobalaminemia is not associated with the presence or development of neoplasia in dogs and cats but may be associated with systemic inflammatory conditions, including pancreatitis, in dogs.