Eight genotypes(A-H) of hepatitis B virus(HBV) have been identified.However,the impact of different genotypes on the clinical course of hepatitis B infection remains controversial.We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV-infected patients from Vietnam,Europe,and Africa.In addition,we analyzed the effects of genotype mixtures on alterations in in vitro viral replication.In Asian patients,seven genotypes(A-G) were detected,with A,C,and D predominating.In European and African patients,only genotypes A,C,D,and G were identified.Genotype mixtures were more frequently encountered in African than in Asian(P =.01) and European patients(P =.06) .In Asian patients,the predominant genotype mixtures included A/C and C/D,compared to C/D in European and A/D in African patients.Genotype A was more frequent in asymptomatic compared with symptomatic patients(P <.0001) .Genotype C was more frequent in patients with hepatocellular carcinoma(HCC;P =.02) .Genotype mixtures were more frequently encountered in patients with chronic hepatitis in comparison to patients with acute hepatitis B(P =.015) ,liver cirrhosis(P =.013) ,and HCC(P =.002) .Viral loads in patients infected with genotype mixtures were significantly higher in comparison to patients with a single genotype(P =.019) .Genotype mixtures were also associated with increased in vitro HBV replication.In conclusion,infection with mixtures of HBV genotypes is frequent in Asia,Africa,and Europe.Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggest that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome. Eight genotypes (AH) of hepatitis B virus (HBV) have been identified. However, the impact of different genotypes on the clinical course of hepatitis B infection remains controversial. We investigated the frequency and clinical outcome of HBV genotypes and genotype mixtures in HBV- infected patients from Vietnam, Europe, and Africa. In addition, we analyzed the effects of genotype mixtures on alterations in vitro viral replication. In Asian patients, seven genotypes (AG) were detected, with A, C, and D predominating. European and African patients, only genotypes A, C, D, and G were identified. Genotypes were more frequently encountered in African than in Asian (P = .01) and European patients (P = .06) predominant genotype mixtures included A / C and C / D, compared to C / D in European and A / D in African patients. Genotype A was more frequent in asymptomatic compared with symptomatic patients (P <.0001). Genotype C was more frequent in patients with hepatocellular carcinoma (HCC; P =. 02). Genotypes were more frequently encountered in patients with chronic hepatitis in comparison with patients with acute hepatitis B (P = .015), liver cirrhosis (P = .013), and HCC (P = .002) patients infected with genotype mixtures were significantly higher in comparison with patients with a single genotype (P = .019). Genotypes were also associated in increased in HBV replication. In conclusion, infection with mixtures of HBV genotypes is frequent in Asia, Africa , and Europe. Differences in the replication-phenotype of single genotypes compared to genotype-mixtures suggesting that co-infection with different HBV-genotypes is associated with altered pathogenesis and clinical outcome.