Objective To examine in a sample of hematopoietic stem cell transplant patients assessed throughout protective isolation (i) levels of anxiety and depression and (ii) pre‐isolation factors (socio‐demographics, biomedical variables and personality traits), which might predict higher levels of anxiety and depression during isolation. Methods The study used a longitudinal prospective design. Anxiety and depression were assessed in 107 participants by the State‐Trait Anxiety Inventory and Self‐rating Depression Scale at admission and weekly at fixed time points throughout isolation. Among pre‐isolation factors, patients' psychological status was evaluated by the Cognitive Behavioral Assessment (2.0). Predictors were explored by random‐effects models. Results One‐tenth of the patients suffered from clinically significant anxiety and depressive symptoms at admission. Although the percentage of depressed patients increased more than twofold after 2 weeks of isolation, that of anxious patients did not significantly change over time. Female gender, higher anxiety and obsessive–compulsive symptoms, intratensive personality traits and lower performance status predicted higher depression during isolation. Conclusions Anxiety and depression represent a relevant problem for hematopoietic stem cell transplant patients during isolation. Early detection of predictors, such as anxiety levels, obsessive–compulsive symptoms and performance status, could help prevent depression via targeted psychological intervention. Copyright © 2012 John Wiley & Sons, Ltd.