Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants. Display omitted •In breakthrough infections, variant-specific cross-neutralizing immunity is limited•Higher antibody titers are observed in severe versus mild breakthrough infections•Delta breakthroughs exhibited 10.8× higher antibody titers compared with Omicron•The rise in antibody titers from Omicron breakthroughs was 1/3 of that from boosting In comparing breakthrough infections from the SARS-CoV-2 Delta and Omicron variants, the latter, though milder than Delta infections, were associated with lower antibody titers and limited cross-neutralizing immunity, suggesting reduced protection against reinfection or infection from a future variant.