Objective: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. Methods: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0·5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. Findings: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17·3% of patients on rivastigmine and 21·4% on placebo progressed to AD (hazard ratio 0·85 [95% CI 0·64-1·12]; p=0·225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0·10 [95% CI -0·63 to 0·44], p=0·726). Serious adverse events were reported by 141 (27·9%) rivastigmine-treated patients and 155 (30·5%) patients on placebo; adverse events of all types were reported by 483 (95·6%) rivastigmine-treated patients and 472 (92·7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. Interpretation: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.