Sequential dengue virus (DENV) infections can result in antibody-dependent disease enhancement. As the Zika virus (ZIKV) and dengue virus envelope proteins are ~40% homologous, Katzelnick et al. explored whether immune interactions among different dengue virus serotypes extends to ZIKV. The authors followed a patient cohort in Nicaragua who have been sequentially exposed to DENV and ZIKV and found that the risk of symptomatic DENV serotype 2 (DENV-2) infection and severe disease was increased by one prior DENV or ZIKV infection. By contrast, multiple DENV infections reduced disease risk. High levels of pre-exisiting anti-DENV antibodies protected against DENV-1, DENV-3 and ZIKV infection, but intermediate levels of DENV or ZIKV antibodies increased the risk of severe disease in DENV-2 and DENV-3 infection, posing a challenge to DENV and ZIKV vaccine development.