Agitation in people with dementia is a growing concern as it causes distress for both patients and their nurses and may contribute to relational disorders. Previous studies involving patients with dementia living in long-term care facilities have reported decreased agitation following massage. The objective of this pilot study was to investigate the effect of hand massage on agitation and biological markers of stress in patients with dementia hospitalized in an acute geriatric psychiatry service. In this randomized controlled trial we included 40 agitated patients with dementia with an intervention group and a control group. The study is designed to test the effect of seven hand massages over three continuous weeks on agitation and levels of salivary cortisol (sC) and alpha-amylase (sAA). Compared to the control group, the intervention group exhibited larger increases in sC and sAA at week 1 from before to after the massage, but larger decreases at week 2 and 3, with a significant group effect for sAA at week 2. Agitation scores were not significantly different between the groups but tended to decrease more in the intervention group than the control group. This study provides first encouraging results suggesting that hand massage might have beneficial effects on stress and agitation in hospitalized patients with dementia. It also highlights the challenges associated with conducting such studies with this complex patient population. Further studies are needed to confirm these findings and the benefits of hand massage as part of routine care for patients with dementia.