Clinical data on the relationships of cytochrome P450 (CYP2) B6 516G>T polymorphisms with efavirenz-induced central nervous system (CNS) side effects and virological response in HIV-infected adults are controversial. We sought to analyze the associations by meta-analysis. To identify eligible studies, we systematically searched PubMed, Embase, ScienceDirect, and Web of Science. The strength of the associations was measured by odds ratio (OR) and effect size (ES) with 95% confidence interval (CI). Seventeen studies comprising a total of 3598 HIV-infected adults were included. The results showed that the CYP2B6-516 GG genotype was significantly associated with a decreased risk of efavirenz-induced CNS side effects compared with the GT and TT genotypes (GG + GT vs. TT: OR = 0.60, 95% CI = 0.41-0.87, P = 0.006; GG vs. GT + TT: OR = 0.68, 95% CI = 0.51-0.91, P = 0.008; GG vs. GT: OR = 0.70, 95% CI = 0.51-0.94, P = 0.018), and there was no significant association between the genetic variants GT and TT (GT vs. TT: OR = 0.82, 95% CI = 0.54-1.26, P = 0.372). However, there was no significant association between CYP2B6-516 GG and GT + TT genotypes in virological response (GT + TT vs. GG: ES = 1.06, 95% CI = 0.95-1.18, P = 0.321; OR = 1.01, 95% CI = 0.65-1.58, P = 0.963). Taken together, our results demonstrated that compared with the normal efavirenz clearance genotype CYP2B6-516 GG, the slow and very slow efavirenz clearance genotypes GT and TT were significantly associated with an increased risk of efavirenz-induced CNS side effects but not an increased virological response. To promote the tolerance of efavirenz, it is better to adjust the dosage of efavirenz according to the polymorphisms of CYP2B6-516 in HIV-infected adults.