Elevated plasma vitamin B12 has been associated with solid cancers, based on a single B12 measurement. We evaluated the incidence of solid cancers following B12 measurement in patients with persistent elevated B12, compared to patients without elevated B12 and to patients with non-persistent elevated B12. The study population included patients with at least two plasma B12 measurements without already known elevated-B12-related causes. Patients with elevated plasma B12 (≥ 1000 ng/L) at first measurement (n = 344) were matched for age and sex with patients having 2 normal B12 measurements (< 1000 ng/L) (NN group, n = 344). The patients with elevated plasma B12 at first measurement were split into 2 groups, according to the presence (EE group, n = 144) or the absence (EN group, n = 200) of persistent elevated plasma B12 at second measurement. We compared the cancer-free survival during 60 months between the groups after adjustment for the other elevated-B12-related causes in a survival competing risk model. Compared to the NN group, a persistent elevated plasma B12 ≥ 1000 ng/mL was strongly associated with the occurrence of solid cancer (HR 5.90 [95% CI 2.79-12.45], p < 0.001), contrary to non-persistent plasma B12 elevation (p = 0.29). These results could help to select patients in whom the screening for solid cancers would be of interest.