Introduction: Reduction of exacerbation frequency plays an increasingly important role in interventions in chronic obstructive pulmonary disease (COPD). To reduce this frequency efficiently, patients at risk for frequent exacerbations need to be identified. Objective: The objective of the study was to identify predictors for frequent exacerbations from multiple domains of COPD during a stable phase of the disease. Methods: Data of multiple domains of COPD were collected from 121 patients with moderate to severe COPD. Patients were divided into infrequent (<2 exacerbations per year) and frequent (≥2 exacerbations) exacerbators. Results: St. George's Respiratory Questionnaire (SGRQ) total score and a course of oral corticosteroid within 3 months prior to the study together predicted best whether patients would be infrequent or frequent exacerbators over the course of the next year. Each unit increase in total SGRQ score was associated with a 3% higher risk of being a frequent exacerbator [odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.00–1.06; P = 0.047]. Patients who received a course of oral corticosteroids in the period of 3 months prior to the study had a three-fold increased risk of being a frequent exacerbator (OR = 3.17; 95% CI: 1.20–8.34; P = 0.02). Furthermore, we observed that a sizable number of patients switched from being a frequent to an infrequent exacerbator and vice versa. Conclusions: Health-related quality of life and a course of oral corticosteroid in the past 3 months are the best predictors of future exacerbator status. The predictive value of the model is, however, still insufficient. Furthermore, our data suggest, in contrast to previous observations, that exacerbation frequency is not a constant feature.