Aims: We investigated whether human umbilical cord blood mononuclear cells (HUCBC) can limit progressive cardiomyopathy in TO2 hamsters. Materials & methods: A total of 22 TO2 1-month-old hamsters were treated with intramyocardial HUCBC, 4 × 10⁶ in Isolyte^®, and 23 TO2 1-month-old hamsters were treated with intramyocardial Isolyte. A total of 16 1-month-old F1B hamsters served as controls and received intramyocardial Isolyte. Echocardiograms were performed on all hamsters prior to and monthly after treatment for 6 months. Heart tissues were then stained with hematoxylin and eosin, Masson’s Trichrome and human leukocyte antibody. Results: In F1B hamsters, left ventricular fractional shortening (FS) and ejection fractions (EF) did not significantly decrease over 6 months. By contrast, in Isolyte-treated TO2 hamsters, FS decreased from 56.2 ± 1.0% to 19.7 ± 3.2% and EF decreased from 89.5 ± 1.4% to 44.9 ± 5.9% at 6 months (both p < 0.0001). The FS and EF in HUCBC-treated TO2 hamsters also progressively decreased over 6 months but the changes were more gradual, especially during the first month after HUCBC treatment when FS was 52.0 ± 1.5% and EF was 89.5 ± 1.4%, which was not significantly different from the FS and EF in the F1B hamsters. Moreover, in the HUCBC-treated hamsters, the FS and EF were 20–30% greater than FS and EF in Isolyte TO2 hamsters at 3 and 5 months (p < 0.01). In Isolyte-treated TO2 hamsters at 6–7 months, fibrosis involved 30.0 ± 5.0% of left ventricle and 35.0 ± 5.0% of septum. By contrast, in HUCBC-treated hamsters, fibrosis involved only 6.5 ± 2.3% of the left ventricle and 6.3 ± 1.8% of septum (p < 0.05). The average number of blood vessels per myocardial microscopic field in HUCBC-treated hearts was 53.5 ± 0.8 versus 46.2 ± 3.0 in Isolyte-treated TO2 hearts (p < 0.05). Conclusion: HUCBC, when given as a single intramyocardial injection, can limit fibrosis and increase heart function over the short term in TO2 hamsters with cardiomyopathy.