Within a multistate viral genomic surveillance program, we evaluated whether proportions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections attributed to the JN.1 variant and to XBB-lineage variants (including HV.1 and EG.5) differed between inpatient and outpatient care settings during periods of cocirculation. Both JN.1 and HV.1 were less likely than EG.5 to account for infections among inpatients versus outpatients (adjusted odds ratio [aOR], 0.60 [95% confidence interval (CI), .43-.84; P = .003] and 0.35 [.21-.58; P < .001], respectively). JN.1 and HV.1 variants may be associated with a lower risk of severe illness. The severity of coronavirus disease 2019 may have attenuated as predominant circulating SARS-CoV-2 lineages shifted from EG.5 to HV.1 to JN.1.