Treatment decisions for patients in the vegetative state often have to be based on the patient's best interests, if the patient's will is not known. Physicians are, however, highly uncertain what kind of treatment is in such a difficult situation the patient's best interests. This article presents new insights from neuroscience and shows how treatment decision making should proceed to reach an ethically justified decision. Pivotal elements are a careful diagnosis using validated behavioural scales, an informed judgment about the existence of awareness and sentience, and an early prognostic assessment. As new imaging techniques and treatment options are not yet clinical standard due to low evidence, the best interests have to be judged in the context of uncertainty. The leading question should be whether the preferred treatment goal can be achieved with a realistic probability and a justifiable benefit-harm-ratio. This has to be judged for the individual patient, considering his personality and communicating with the family members. There cannot be a general answer to the question of best interests in the vegetative state, but only an individual answer in shared responsibility and based on the particular features of a special case.