Long-term use of aspirin as an antithrombotic agent is limited by its toxicity in the gastrointestinal tract. Even very low doses of aspirin can markedly increase the risk of gastrointestinal bleeding and ulceration. Addition of a nitric oxide (NO)-releasing moiety to non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to greatly reduce their ulcerogenic properties as well as their renal toxicity. We proposed that similar derivatisation of aspirin may yield a potent, gastrointestinal-sparing antithrombotic drug. Two prototype compounds (NCX-4215 and NCX-4016; Nicox SA) have been evaluated thus far. Each shows comparable or better anti-aggregatory activity to aspirin while not inducing detectable gastric damage. Current studies are aimed at determining what the optimal balance is between nitric oxide release and inhibition of thromboxane synthesis to achieve good antithrombotic activity with low toxicity. NO-aspirin derivatives appear to offer great potential as gastrointestinal-sparing antithrombotic drugs.