HIV-1 controllers are patients who control HIV-1 viral replication without antiretroviral therapy. Control is achieved very early in the course of infection, but the mechanisms through which viral replication is restricted are not fully understood. We describe a patient who presented with acute HIV-1 infection and was found to have an HIV-1 RNA level of <100copies/mL. She did not have any known protective HLA alleles, but significant immune activation of CD8+ T cells and natural killer (NK) cells was present, and both cell types inhibited viral replication. Virus cultured from this patient replicated as well in vitro as virus isolated from her partner, a patient with AIDS who was the source of transmission. Virologic breakthrough occurred 9months after her initial presentation and was associated with an increase in CD4+ T cell activation levels and a significant decrease in NK cell inhibitory capacity. Remarkably, CD8+ T cell inhibitory capacity was preserved and there were no new escape mutations in targeted Gag epitopes. These findings suggest that fully replication-competent virus can be controlled in acute HIV-1 infection in some patients without protective HLA alleles and that NK cell responses may contribute to this early control of viral replication. •We show that an HIV-1 controller was infected with pathogenic virus yet maintained low viral loads during primary infection.•She had activated NK cells and CD8+ T cells and both cell types suppressed HIV-1 replication shortly after infection.•She eventually lost control of viral replication, and this was associated with a reduction in NK cell suppressive activity. HIV-1 controllers are patients who control the virus without HIV-1 medications. These patients may teach us how to design a vaccine against HIV-1. Little is known about how the virus is controlled in the early phase of infection in these patients. Here we show that a recently infected HIV-1 controller had a strong natural killer cell response to the virus. Interestingly, she lost control of the virus 9months later and her natural killer cell response to the virus was diminished. Our work suggests that natural killer cells may have contributed to viral control in the early phase of infection.