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Background and Aim: Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation, the upregulation of CYP2E1 is involved in development of nonalcoholic steatohepatitis (NASH). We aimed to explore the relationship between CYP2E1‐333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). Methods: We studied 438 patients with biopsy‐proven NAFLD. NASH was defined as NAFLD Activity Score ≥ 5 with existence of steatosis, ballooning, and lobular inflammation. CYP2E1‐333A>T (rs2070673) was genotyped by matrix‐assisted laser desorption ionization‐time of flight mass spectrometry. Serum cytokines related to inflammation were measured by the Bio‐plex 200 system to investigate possible mediating factors involved in the process. Results: The TA genotype of rs2070673 had a higher prevalence of moderate/severe lobular inflammation (27.6% vs 20.3% vs 13.3%, P < 0.01) and NASH (55.7% vs 42.4% vs 40.5%, P < 0.01) compared with the AA and TT genotypes, respectively. In multivariable regression modeling, the heterozygote state TA was associated with moderate/severe lobular inflammation (adjusted odds ratio: 2.31, 95% confidence interval 1.41–3.78, P < 0.01) or NASH (adjusted odds ratio: 1.82, 95% confidence interval 1.22–2.69, P < 0.01), independently of age, sex, common metabolic risk factors, and presence of liver fibrosis. Compared with no‐NASH, NASH patients had significantly higher levels of serum interleukin‐1 receptor antagonist, interleukin‐18, and interferon‐inducible protein‐10 (IP‐10), whereas only IP‐10 was increased with the rs2070673 TA variant (P = 0.01). Mediation analysis showed that IP‐10 was responsible for ~60% of the association between the rs2070672 and NASH. Conclusions: The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP‐10 levels. [ABSTRACT FROM AUTHOR]