The mechanisms underlying the three main outcomes of acute HBV infection – acute self-limited hepatitis (AVHB), acute liver failure (HBV-ALF), acute reactivation in chronic hepatitis B (CHB-ALF) – remain undefined. We used 216 serial serum samples from 46 patients from the US ALF Study Group and HBRN to investigate virus-host interplay, comparing the three phenotypes: 13 AVHB, 25 HBV-ALF and 8 CHB-ALF. HBV-ALF was separated into early (<10d onset to encephalopathy, HE; N=7), HBV-ALF late (>10d, N=11) and acute liver injury (ALI; INR 2.0, no HE, N=7). Among HBV-ALF, 41% died or required transplantation. We tested HBV genotype, quantification of HBsAg, IgM anti-HBc, anti-HBs, HBcrAg, HBV DNA, HBV RNA, HDV RNA. NGS was performed in 196 samples (876 nucleotides, including pre-core/core). We also analyzed 19 cytokines. We found: (a) HBsAg was lower in HBV-ALF than AVHB, but similar to CHB-ALF; (b) IgM anti-HBc titers were higher in HBV-ALF than CHB-ALF or AVHB; HBeAg was detected in 61%; (c) HBcrAg was higher in CHB-ALF than HBV-ALF but similar to AVHB; (d) HBV DNA levels were similar; (e) HBV RNA was undetectable in AVHB, but low in 20% of HBV-ALF and 75% of CHB-ALF; (f) NGS documented a highly homogeneous viral population in HBV-ALF, with the lowest number of variants in ALF early and the most diverse population in CHB-ALF. Genotype A was detected in 29 cases (16 ALF, 9 AVHB, 4 CHB-ALF) whereas other genotypes were less represented. The precore mutation was not found in genotype A but was present in other genotypes. Distinct cytokine profiles were observed. HBV-ALF late outcomes were very poor (9/11 died/OLT) and significantly different from HBV-ALF early (3/7). In conclusion, HBV genotype A circulates as a highly homogeneous population lacking the precore mutant unlike other genotypes. Distinct serologic, virologic and cytokine profiles differentiate classic AVHB from HBV-ALF and CHB-ALF.