Purpose: We hypothesized that increased level of serum beta 2-microglobulin (beta 2M) is an independent factor associated with higher mortality in hospitalized patients with exacerbated chronic obstructive pulmonary disease (COPD). Patients and Methods: We retrospectively analyzed 488 hospitalized patients with exacerbated COPD as the first diagnosis at Beijing Chao-Yang hospital, P. R. China between December 31st, 2012 and December 28th, 2017. Concentrations of serum beta 2M and other clinical indexes were measured or collected on admission, and all patients were followed up to 90 days. The relationship between beta 2M and 30- and 90-day all-cause mortality was explored by Cox regression analysis adjusted for age, C-reactive protein values, N-terminal pro-brain natriuretic peptide/100, respiratory failure [RF, defined as partial arterial oxygen pressure (PaO2) <60 mmHg on room air or PaO2 over the fraction of inspired oxygen (PaO2/FiO(2)) < 300], eosinopenia, consolidation, and acidaemia. Results: Median concentrations of beta 2M were significantly higher in non-survivals compared to survivals within 30 days (4.11 mg/L (IQR 3.10-6.60) vs 2.79mg/L (IQR 2.13-3.76), P < 0.001) and 90 days (3.79 mg/L (IQR 2.61-6.69) vs 2.79 mg/L (IQR 2.13-3.73), P < 0.001). Serum levels of beta 2M were correlated with 30-day and 90-day mortality in overall exacerbated COPD patients, with hazard ratios (HRs) of 1.09 (95% CI 1.04-1.14, P = 0.001) and 1.09 (95% CI 1.05-1.14, P < 0.001). In exacerbated COPD patients without RF and with RF, the HRs were 1.06 (95% CI 0.995-1.137, P = 0.069) and 1.14 (95% CI 1.02-1.27, P = 0.021) for 30-day mortality, 1.09 (95% CI 1.02-1.15, P = 0.010) and 1.14 (95% CI 1.03-1.26, P = 0.014) for 90-day mortality, respectively. Conclusion: Our data showed that concentrations of serum beta 2M were associated with an increased risk of mortality, suggesting that beta 2M might be a valuable predictor of poor prognosis for hospitalized patients with exacerbated COPD.