In the recently published SPS3 trial, clopidogrel plus aspirin increased mortality compared with aspirin alone in patients with lacunar cerebral infarcts. A detailed review of currently available trial data on this dual-antiplatelet strategy, having taken the between-trial variation in mortality in the various control groups into account, indicates lethal toxicity which also occurs in patients with coronary atherosclerosis. The recently observed benefit of an alternative P2Y12 receptor antagonist (ticragelor) on survival as compared with clopidogrel suggests that the toxicity of the clopidogrel/aspirin combination likely results from an 'off-target' effect. The exact nature of this 'off-target' effect is currently unknown. The lack of a survival benefit in combination with the frequent occurrence of serious bleeding complications requires the cessation of the use of clopidogrel in combination with aspirin. The question whether clopidogrel should be replaced by an alternative P2Y12 receptor antagonist needs to be answered by future trials.