Background The interleukin‐33 (IL‐33)/suppressor of tumorigenicity 2 (ST2) pathway is suggested to play an important role in fibrosis, remodelling and the progression of heart failure (HF). Increased soluble (sST2) levels are associated with adverse outcome in the average HF population. Less is known about sST2 levels in end‐stage HF. Therefore, we studied sST2 levels in end‐stage HF and the effect of unloading by left ventricular assist device (LVAD) support on sST2 levels. Method and results Serial plasma measurements of sST2 were performed pre‐implantation and 1, 3 and 6 months after (LVAD) implantation in 38 patients. sST2 levels were elevated in end‐stage HF just prior to LVAD implantation (74.2 ng/mL IQR 54.7‐116.9; normal <35 ng/mL) and decreased substantially during LVAD support, to 29.5 ng/mL IQR 24.7‐46.6(P < .001). Patients with INTERMACS profile I had significantly higher sST2 levels compared to patients in profile II and profile III. A moderate correlation was found between sST2 and C‐reactive protein (r = .580, P < .010). Conclusion Levels of sST2 are elevated in end‐stage HF patients with variability that suggests multiple inputs to a pro‐inflammatory and pro‐fibrotic pathway. Cardiogenic shock and increased C‐reactive protein levels are associated with higher sST2 levels. LVAD support results in a significant drop in sST2 levels with normalization within 3 months postimplantation. This suggests that LVAD support leads to lessening of fibrosis and inflammation, which might eventually be used to target medical policy: explantation of the LVAD versus permanent use or cardiac transplantation.