The most reliable predictor of a sustained virological response in patients with persistently normal ALT has not been identified. We analysed 17 patients with genotype 1 chronic HCV who underwent therapy with pegylated interferon alfa 2b and ribavirin for 48 weeks. Two patients discontinued therapy within 28 days because of side effects and the remaining 15 patients were analysed in detail. An analysis of on treatment virological response using area under the receiver operating characteristic analyses showed that a 2 log drop in HCV RNA at day 28 was the best predictor of a sustained virological response and a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a sustained virological response. Introduction of this early discontinuation rule in patients with normal ALT would allow nearly half of the patients to discontinue futile therapy at an early stage.