Aims: Allogeneic stem cell therapy is more logistically suitable compared with autologous cell therapy for large-scale patient treatment. We aim to investigate the clinical safety and efficacy profile of the allogeneic adipose tissue derived mesenchymal stromal cell product (CSCC_ASC) as an add-on therapy in patients with chronic non-ischaemic heart failure with reduced left ventricular ejection fraction (HFrEF) < 40%. Methods and results: This is a single-centre investigator-initiated randomized phase I/II study with direct intra-myocardial injections of 100 million allogeneic CSCC_ASC. A total of 30 HFrEF patients with New York Heart Association (NYHA) class ≥II despite optimal anticongestive heart failure medication and plasma NT-proBNP > 300 pg/mL (>35 pmol/L) were included and randomized 2:1 to CSCC_ASC or standard care. The primary endpoint left ventricular end systolic volume (LVESV) and other echo related parameters were analysed by an investigator blinded for treatment allocation. No difference in serious adverse events was observed between groups. LVESV decreased significantly from baseline to 6 months follow-up in the ASC group (153.7 ± 53.2 mL and 128.7 ± 45.6 mL, P < 0.001) and remained unchanged in the standard care group (180.4 ± 39.4 mL and 186.7 ± 48.9 mL, P = 0.652). There was a significant difference between the groups in LVESV change (31.3 ± 11.0 mL, P = 0.009). The difference from baseline to follow-up between the two groups in left ventricular end diastolic volume (LVEDV) was 18.7 ± 12.4 mL, P = 0.146 and in left ventricular ejection fraction (LVEF) −7.8 ± 2.1%, P = 0.001. Considering the baseline values of LVESV, LVEDV and LVEF as covariates, the difference between groups for change from baseline to follow-up resulted in a P-value of 0.056, 0.076, and 0.738, respectively. NYHA class and self-reported health did also improve significantly in the ASC group compared with the standard care group (0.7 ± 0.2, P = 0.001 and −12.8 ± 5.3, P = 0.025; respectively). There was no difference in NT-proBNP (−371 ± 455 pmol/L, P = 0.422) or in 6 min walk test (12 ± 31 m, P = 0.695) between groups. Conclusions: Intramyocardial injections of allogeneic CSCC_ASC in patients with chronic non-ischaemic HFrEF was safe and improved LVESV, LVEF, NYHA class, and self-reported health compared with standard care group.