Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system. Smoking is a major risk factor of COPD. Neurotransmitter system genes were tested for association with COPD using DNA samples from COPD patients (N = 601) and healthy subjects (N = 617). SNPs of GRIK3 (rs534131), GRIN2B (rs7301328 and rs1805476), GRIA1 (rs2195450), GRIN1 (rs6293), GABBR2 (rs3750344), BDNF (rs6265 and rs11030107), and ANKK1 (rs1800497) were genotyped by real-time polymerase chain reaction (PCR). Significant associations were detected for GRIK3 (rs534131) (P = 0.009, OR = 1.42 in a dominant model), GRIA1 (rs2195450) (P = 0.015, OR = 1.35 in a dominant model), GRIN1 (rs6293) (P = 0.036, OR = 0.79 in a log-additive model), and GRIN2B (rs7301328) (P = 0.0009, OR = 0.54 in a recessive model). GRIK3 (rs534131) (P = 0.0001, OR = 1.68 in a dominant model) and GRIN2B (rs7301328) (P = 0.001, OR = 0.52 in a recessive model) were significantly associated with COPD only in smokers. Associations of GRIN1 (rs6293) (P = 0.0001, OR = 0.36 in a dominant model), GRIA1 (rs2195450) (P = 0.0018, OR = 2.40 in a log-additive model), and BDNF (rs11030107) (P = 0.005, OR = 2.86 for TT) with COPD were detected in nonsmokers. Lower smoking index were observed in carriers of the GRIK3 (rs534131) genotype GG and GRIA1 (rs2195450) genotype GG (P = 0.028 and 0.0001, respectively). The level of nicotine dependence was significantly higher in carriers of the rare allele A of GRIK3 (rs534131A>G) and the genotype GC of GRIN2B (rs7301328C>G) (P = 0.011 and 0.023, respectively). Informative genotype and allele combinations significantly associated with COPD were identified using the APSampler algorithm and included GRIN2B rs2268132*T, GRIN2B rs7301328*G, GRIN2B rs1805476*C, ANKK1 rs1800497*G, GABBR2 rs3750344*A, CHRNA5 rs16969968*T, CHRNA3 rs1051730*A, HTR2A rs6313*CC, and GRIA1 rs2195450*G.