Cholinesterase inhibitors (ChEI) are currently the mainstream symptomatic treatment of patients with Alzheimer's disease (AD). To this end, the response to the treatment with ChEI is clinically difficult to predict. Several demographic, clinical and biological variables have been proposed as pre-treatment predictors of long-term therapy efficacy. The aim of this study was to confirm our initial observations of a significance of change in plasma levels of b-amyloid (Aβ) peptides after initial treatment with rivastigmine for predicting clinical response to ChEI. Fifty four carefully selected subjects (37 females) satisfying criteria for mild (N=25) or moderate (N=29) AD were included in the study. Rivastigmine was prescribed at the initial dose of 3 mg/day b.i.d.; the dose was escalated to the maximum tolerated one in at least 4-week intervals. The response to treatment was assessed using ADAS-Cog scale. The whole blood samples were collected twice: before the first rivastigmine dose and at the 2nd week on active treatment. Levels of Ab1-40 and Ab1-42 were measured in plasma using a commercially available ELISA. We confirmed that higher initial disease severity (higher ADAS-Cog scores) and the increase in the concentration of plasma Aβ1-42 peptide following 2 weeks of treatment with an initial dose of rivastigmine increased the chance of a clinically meaningful response to ChEI therapy in AD patients after 2 years of follow-up. To conclude, a change in plasma Aβ1-42 level might constitute a novel biochemical predictor of long-term rivastigmine treatment efficacy in AD.