Alzheimers disease is a relentlessly progressive disease with cognitive, functional and behavioral changes over time. Current research into new drugs is focused on agents that will prevent, slow down and/or halt the progress of the disease process. Melissa officinalis has been used in herbal medicine for many centuries. It has been suggested, on the basis of traditional medicine, its in vitro cholinergic binding properties and modulation of mood and cognitive performance in humans, that Melissa officinalis might potentially provide a novel natural treatment for Alzheimers disease. The objective of this study was to assess the efficacy and safety of Melissa officinalis extract using a fixed dose (60 drops/day), in patients with mild to moderate Alzheimers disease, over the four months. This was a 4-month, parallel group, placebo controlled trial undertaken in 3 centres in Tehran, Iran. Patients with mild to moderate Alzheimers disease aged between 65-80 years (n=42, 18 women) with a score of ? 12 on the cognitive subscale of Alzheimers Disease Assessment Scale (ADAS-cog) and ? 2 on the Clinical Dementia Rating (CDR) were randomised to placebo or fixed dose of Melissa officinalis extract. Over the 16 weeks, the main efficacy measures were the change in the ADAS-cog and CDR-SB scores compared to baseline. In addition, side effects were systematically recorded throughout the study using a checklist. At 4 months, Melissa officinalis extract produced a significant better outcome on cognitive functions than placebo (ADAS-cog: d.f. = 1, F= 6.93, P=0.01) (CDR: d.f.= 1, F = 16.87, P< 0.0001). There were no significant differences in the two groups in terms of observed side effects except agitation that was more often in the placebo group (P = 0.03). The results of this study indicate the efficacy of Melissa officinalis extract in the management of mild to moderate Alzheimers disease. Moreover, the effect of Melissa officinalis on agitation of patients, may well prove a novel natural treatment for Alzheimers disease.