Rationale: Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) are a major cause of morbidity and mortality in COPD. Objectives: The marked heterogeneity in the host defense mechanisms may be attributed to the single nucleotide polymorphisms (SNPs) in the inflammatory chemokines that show enhanced expressions in the airway of AECOPD. Methods: We investigated four SNPs in CCL11, CCL1, and CCL5 genes with relation to the frequency and severity of AECOPD in the retrospective and prospective study of a cohort of 276 male patients with COPD. Measurements and Main Results: In the retrospective study for two years, one SNP (NCBI SNP reference: rs2282691) in the predicted enhancer region of CCL1 gene, encoding a chemotactic factor for a series of leukocytes, was significantly associated with the frequency of AECOPD in a dominant model {Fisher's exact test [odds ratio (OR) (95% confidence interval): 2.70 (1.36 - 5.36), P=0.004], logistic regression [OR: 3.06 (1.46 - 6.41), P=0.003], and Kruskal-Wallis test (P=0.003)}. In the prospective study for 30 months, the 'A' allele was a significant risk allele for the severity of AECOPD with gene dosage effect [Kaplan-Meier method with log-rank test; AA vs. TT; log-rank statistic: 7.67, P=0.006. Cox proportional hazards regression method; OR: 5.93 (1.28 - 27.48), P=0.023]. The electromobility shift assay showed C/EBP, a key transcriptional factor in response to pulmonary infections, binds to the 'T' allele, but not to the 'A' allele. Conclusions: Variants in CCL1 gene are associated with susceptibility to AECOPD through their potential implication in the host defense mechanisms against AECOPD.