Background In this prospective multicenter study, we investigated cancer‐and‐treatment–specific distress (CTXD) and its impact on symptoms of posttraumatic stress disorder (PTSD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods Patients were consulted before (T0, N = 239), 3 (T1, N = 150), and 12 months (T2, N = 102) after HSCT. Medical (eg, diagnosis and pretreatment) and demographic information, CTXD and PTSD (PCL‐C) were assessed. Results Random intercept models revealed that the sum score of CTXD was highest pre‐HSCT (T0), decreased by T1 (γ = −.18, 95% CI [−.26/−.09]), and by T2 (γ = −.10, 95% CI [−.20/−.00]). Uncertainty, family strain, and health burden were rated most distressing during HSCT. Uncertainty and family strain decreased from T0 to T1 (γ = −.30, 95% CI [−.42/−.17]; γ = −.10, 95% CI [−.20/−.00]) and health burden from T1 to T2 (γ = −.21, 95% CI [−.36/.05]). Women were more likely to report uncertainty (γ = .38, 95% CI [.19/.58]), family strain (γ = .38, 95% CI [.19/.58]), and concerns regarding appearance and sexuality (γ = .31, 95% CI [.14/.47]) than men. Uncertainty (γ = .18, 95% CI [.12/.24]), appearance and sexuality (γ = .09, 95% CI [.01/.16]), and health burden (γ = .21, 95% CI [.14/.27]) emerged as predictors of PTSD symptomatology across the 3 assessment points. Conclusions Our data provide first evidence regarding the course of 6 dimensions of CTXD during HSCT and their impact on PTSD symptomatology. Specifically, results emphasize the major burden of uncertainty pre‐HSCT and the impact of uncertainty and concerns regarding appearance and sexuality on PTSD symptomatology.