Background: Chronic obstructive pulmonary disease (COPD) is associated with systemic inflammation and frequent exacerbations, thus, leading to disease progression and increased morbidity. Vitamin D deficiency has been suggested to be a contributing factor to COPD inflammation and exacerbations. Aim: To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels, systemic inflammation and exacerbation frequency among patients with COPD GOLD group E. Methods: A cross-sectional study was conducted on 111 patients with stable COPD. Patients were divided into two groups based on their serum 25(OH)D levels (<50 nmol/L vs. ≥50 nmol/L). Data on exacerbation frequency the past year, inflammatory markers, dynamic lung volumes and symptom burden were collected. Results: Patients with low serum 25(OH)D (<50 nmol/L) had significantly higher CAT-score and level of serum-high sensitivity (hs)-CRP and exhibited significantly more exacerbations compared to those with higher levels (p < 0.001, p < 0.001 and p < 0.0001, respectively). Furthermore, lower vitamin D levels were associated with higher CAT scores (r = -0.30; p < 0.01) and level of serum hs-CRP (r = -0.25; p < 0.01) and significantly more exacerbations (r = -0.74; p < 0.0001). Conclusion: Low vitamin D levels are significantly associated with greater symptom burden, elevated hs-CRP and increased exacerbation frequency in COPD patients group E. These findings suggest that monitoring and treating vitamin D deficiency may be beneficial in COPD patients with frequent exacerbations.