The serum levels of matrix metalloproteinases (MMPs) increase during chronic heart failure (HF) and the MMP-2 are related to a poor prognosis. However, the roles of MMP-2 in acute HF (AHF) remain unclear. We investigated the change and clinical significance of MMP-2 in these conditions. The serum levels of MMP-2 were measured in 83 AHF patients before starting treatment (day 1), 3 (day 3) and 7 (day 7) days after admission, and before discharge (predischarge). MMP-2 decreased rapidly and significantly from day 3 to day 1 (902.9 ± 304.2 versus 1220.4 ± 330.5 ng/mL; P < 0.0001), whereas that of MMP-2 was not significantly different on day 7 and at predischarge (894.7 ± 278.9 and 920.0 ± 269.6 ng/mL, respectively) compared to day 3. We evaluated the relationships between ΔMMPs, defined as the changes in MMPs from day 1 to day 3 and HF events including cardiac death, readmission to hospital for HF, and uncontrollable HF. The MMP-2 value was significantly (P = 0.004) more decreased in the event-free group (381.4 ± 256.5 ng/mL) than in the event group (211.9 ± 225.5 ng/mL) between day 1 and day 3. The results of the multivariate logistic regression model for predicting HF events found that the specific factor for HF events was ΔMMP-2. Cutoff values of ΔMMP-2 were determined and event-free curves were constructed. Kaplan-Meier curves showed that the prognosis was significantly better among the patients with reductions in ΔMMP-2 values of more than 342 ng/mL. The serum levels of MMP-2 decreased with improvements in AHF. Rapid decreases in MMP-2 may be important for a better clinical outcome in patients with AHF.