<b><i>Background: </i></b><i>CYP1A1</i> and <i>CYP2D6</i> are important genes encoding enzymes involved in the metabolism of toxic chemicals and carcinogens. However, inconclusive results for the association between <i>CYP1A1</i> and <i>CYP2D6</i> polymorphisms and the risk of head and neck squamous cell carcinoma (HNSCC) have been reported. We conducted a meta-analysis to evaluate the association of <i>CYP1A1</i> and <i>CYP2D6</i> polymorphisms with the risk of HNSCC. <b><i>Methods: </i></b>A database search yielded 19 relevant studies. 3 polymorphisms were included in the meta-analysis: <i>CYP1A1</i>, <i>CYP2D6*4</i> and <i>CYP2D6*10</i>. Random or fixed effect models were used in the analysis. <b><i>Results: </i></b>The <i>CYP1A1</i> polymorphism was associated with HNSCC (for m1m1 vs. m1m2: odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.030-1.542, p_{heterogeneity} = 0.025; for the recessive model: OR = 1.316, 95% CI = 1.065-1.625, p_{heterogeneity} = 0.001). The analysis showed evidence for association between the <i>CYP2D6*4</i> polymorphism and HNSCC in Asian populations; however, negative results were also observed in other models. A significant association was also observed between <i>CYP2D6*10</i> polymorphism and HNSCC risk. <b><i>Conclusions: </i></b>The current study demonstrates that the <i>CYP1A1</i> and CYP2D6 polymorphisms are associated with susceptibility to both development and progression of HNSCC.