Background. The mechanisms determining the outcome in acute HBV infection: self-limited hepatitis (AVHB), acute liver failure (HBVALF), and reactivation (acute-on-chronic) (CHBALF), are poorly understood. We used sera from the US Acute Liver Failure Study Group and Hepatitis B Research Network to study virus-host interplay, comparing the 3 phenotypes. Methods. 216 serial serum samples from 46 patients from well-characterized HBV phenotypes—13 with AVHB, 25 with HBVALF and 8 CHBALF were analyzed for HBV genotype, quantification of HBsAg, IgM anti-HBc and anti-HBs titers, as well as HBV core-related antigen (HBcrAg), HBV DNA, HBV RNA. Additionally, 19 cytokines were tested serially in the three groups. We also separated the HBVALF group into early (<10d onset to encephalopathy, HE; N=7), HBVALF late (>10d, N=11) and acute liver injury (INR 2.0, no HE; ALI, N=7). Among HBVALF, 41% died or required transplantation: all AVHB and ALI patients survived. Titers are given in logs. Results. The most significant serological differences were: (a) IgM anti-HBc titers were higher in HBVALF (median, 6.6 log) than CHBALF (1.3) or AVHB (4.7); (b) HBsAg was lower in HBVALF (3.7) than in AVHB (4.7), but similar to CHBALF (3.4); (c) HBcrAg was higher in CHBALF (7.0) than HBVALF (5.9) but similar to AVHB (6.6); (d) HBV RNA was undetectable in AVHB, but at low levels in 20% of HBVALF and in 75% of CHBALF (4.0). All were positive for HBV DNA without significant differences between groups. Distinct cytokine profiles were observed. AVHB demonstrated significant induction of the IFN-inducible chemokine IP10 and MIP-1b, whereas HBVALF had significantly higher levels of the pro-inflammatory cytokines IL-4, IL-6, MCP-1, sCD137 and TNF-a. CHBALF showed the highest levels of IL-8, HBcrAg and HBV RNA along with the lowest IgM anti-HBc titers. These patterns persisted after admission. Within the HBVALF group, distinct signatures were observed comparing HBVALF early with ALF late and ALI. Outcomes for the HBVALF late presenters were very poor (9/11 died/OLT) and significantly different from early presenters (3/7). Spontaneous survival correlated with significantly higher values of TNF and IP10 at admission. Conclusions. There are distinct serologic, virologic and cytokine profiles differentiating classic AVHB from HBVALF and CHBALF. Moreover, it provides the first evidence that early and late ALF differ in their profiles and outcomes suggesting different mechanisms of pathogenesis.