The interactions among hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) were studied by measuring HBV-DNA and HCV-RNA levels and by determining the influence of viral genotypes and mutations in HBV basal core promoter (BCP) and precore regions. We included 65 consecutive patients, 25 HBV/HCV, 18 HBV/ HDV, and 22 HBV/HCV/HDV. Controls consisted of 55 patients with chronic HBV and 55 with chronic HCV infection. HBV-DNA and HCV-RNA levels were lower in coinfections than in single infections (P < .05). HBV/HCV coinfection was associated with lower HBV viremia (8.2 ؋ 10 4 copies/ mL) and lower HCV-RNA levels (7 ؋ 10 5 IU/mL), than the corresponding control group (P < .05), with more marked decrease in HBV replication (P < .05). Moreover, in HBV/ HCV coinfection and in triple coinfection we observed an inverse relationship between HBV-DNA and HCV-RNA levels (P < .05). HBV/HDV coinfection was associated with lower HBV viremia (2.5 ؋ 10 4 copies/mL) than that found in HBV infection (P < .05). Patients with triple coinfection showed lower HBV-DNA and HCV-RNA levels than control groups (P < .05). Prevalence of precore mutations was lower in HCV coinfections (P < .05). No significant association was observed between HCV-RNA levels and HBV precore mutations, BCP mutations or HBV genotypes, or between HBV-DNA levels and HCV genotypes (P < .05). In conclusion, HCV exhibited stronger inhibitory action in the reciprocal inhibition seen in HBV/HCV coinfection. HDV was the dominant virus in HBV/HDV coinfection and in triple coinfection, and had a greater unfavorable influence on HCV than on HBV replication. The reciprocal inhibition of viral replication seemed to be little influenced by the inherent genomic factors studied. (HEPATOLOGY 2001;34:404-410.)Hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) are the most common causes of chronic liver disease. All 3 viruses are transmitted by exposure to infected blood and it is not unusual to find patients coinfected with HBV and either HCV or HDV, or with all 3 viruses. 1 Although the phenomenon of viral interference in mixed infection has been described previously, the interplay between these viruses and the mechanisms regulating this interplay are not completely defined, and it is not clear which is the strongest in terms of mutual replicative suppression. 2 Studies in dual HBV and HCV infection have yielded conflicting data, with some reports suggesting that HCV possesses the strongest suppressing effect 3,4 and others attributing the dominant role to HBV. 5,6 Moreover, an alternative replicative dominance, probably because of mutual interference, has also been suggested. 6,7 In HBV and HDV dual chronic infection, evidence from animal experiments and human clinical studies indicates that HBV replication diminishes as a result of HDV superinfection. 8 Finally, contrasting results regarding viral replication have been observed in triple infection. In this context, early studies reported serologic and immunohistologic fi...