Introduction: COPD is a leading cause of hospitalization and death. Epidemic respiratory viruses have been associated with exacerbations of COPD. Recently it has been reported that HSV-1 can cause deterioration in COPD. In ventilated patients Herpes Simplex Virus-1 (HSV-1) is frequently identified and is associated with an increased mortality. We wished to establish if HSV-1 in COPD was associated with medication, disease severity and subsequent mortality. Methods: Patients hospitalized with an exacerbation of COPD were recruited within 24 hours of admission. Their medication was documented and spirometry was performed. Sputum was obtained and lyzed in dithiothreitol. Nucleic acids were extracted and specimens were tested for the presence and number of copies HSV-1 using real-time PCR. Chest radiographs were reported through the routine clinical service. Patients were followed up at a mean of 56 months. Cause of death was assessed by ICD code on the death certificate. Results: One hundred and twelve patients with exacerbations of COPD were recruited. HSV-1 was detected in 21 patients (19%). This was associated with higher maintenance doses of inhaled steroids (1,000 mcg/day vs. 500 mcg/day, P< 0.005) prior to admission. Radiographic features of pulmonary infiltrates were more frequent (38% vs. 15.6%, p< 0.05). They had worse lung function with FEV1 (0.54 ± 0.23 vs. 0.92 ± 0.48 L, p< 0.05). HSV-1 during exacerbations was associated with increased mortality on follow-up, hazard ratio 2.3 (1.3-4.0) p< 0.0001. The median survival was 2.08 (CI 1.00-3.16) years in the group with HSV-1 compared to 5.5 (CI 4.68-6.32) without the virus. There were significantly higher numbers of pulmonary related deaths in those with HSV-1 (72% vs. 41%, p< 0.05). Conclusion: HSV-1 is frequently detected in the sputum of COPD patients. It is more commonly found in patients taking higher doses of inhaled steroid. The presence of HSV-1 is associated with increased subsequent pulmonary mortality.