von Hippel-Lindau disease (vHL) is a hereditary multisystem cancer syndrome requiring lifelong prophylactic surveillance. Current surveillance recommendations rely on best medical judgement and no evidence of effect exists. We aimed to evaluate the capability of surveillance in manifestation detection, before these turn symptomatic, in order to prevent disabling or even fatal outcomes. We focus on surveillance of central nervous system (CNS) hemangioblastomas, retinal hemangiomas and renal cell carcinoma (RCC) as these have the most severe consequences. On the basis of full medical records from 54 living vHL-mutation carriers, risks of intercurrent manifestations in-between surveillance examinations were determined and clinical consequences of surveillance findings evaluated. Current recommendations of annual ophthalmic and abdominal examinations corresponded to acceptably low intercurrent manifestation risks (1.7% and 1.2%, respectively), whereas recommendations of biennial CNS imaging corresponded to a risk of 7.2%. Annual CNS examinations, however, significantly reduces this risk to 2.7%. Furthermore, most CNS manifestations found due to surveillance (71%, 106 of 150) had clinical consequence for the patient. Also, pre-symptomatic surveillance increased cumulative incidence of clinical vHL diagnosis from 46% to 72% and from 89% to 94% by age 30 and 50 years, respectively. The present results promote optimization of surveillance, expectantly improving clinical vHL outcomes.