A systematic review was carried out to evaluate whether the use of N-acetylcysteine to improve lung function in patients with cystic fibrosis is supported by published evidence. Medline and the Cochrane Library were searched and the reference lists of all retrieved papers and of relevant chapters of three major textbooks were scanned. Data on lung function (forced expiratory volume in one second (FEV1)) were extracted from controlled clinical trials and pooled as weighted mean differences for analysis. Twenty-three studies, mostly uncontrolled clinical observations, were retrieved. Only three randomized controlled clinical trials on nebulized N-acetylcysteine in cystic fibrosis were found, not showing any beneficial effect on lung function. Six randomized controlled clinical trials on oral N-acetylcysteine in cystic fibrosis were found, with a total number of 181 patients. There was a tendency towards a beneficial effect on lung function of oral N-acetylcysteine therapy on FEV1 but it was small (2.3%, 95% CI from (-0.3 to 4.9% of predicted) and of doubtful clinical relevance. In all studies, follow-up was 3 months or shorter. In conclusion, at present there is no evidence supporting the use of N-acetylcysteine in cystic fibrosis, although a beneficial effect with long-term use of N-acetylcysteine in cystic fibrosis cannot be excluded.