Worldwide, 71 million people are chronically infected with HCV, and the WHO estimates that 400,000 people die from HCV-associated liver diseases each year. While 15–45% of infected individuals are able to spontaneously clear the infection without the need for therapy, 55–85% develop a chronic infection. Since in western industrialized countries the most important risk factor to acquiring HCV is intravenous drug use, we use a cohort of people who inject drugs (PWID) to gain novel insight into the contribution of the innate as well as adaptive immune system to HCV infection outcome. We comparatively analyze patients that develop chronic infection, individuals with spontaneous immune control of HCV infection, and individuals that remain anti-HCV seronegative despite continuous high-risk behaviour.There is growing evidence that natural killer (NK) cells, which are part of the innate immune system, contribute to HCV control. Genetic association studies linked certain combinations of NK cell receptors and their ligands with beneficial HCV infection outcome. We performed a cohort study to analyze how the combination of killer-cell immunoglobulin-like receptors (KIRs) that regulate NK cell function and their ligands impact the HCV infection outcome in PWID. The genetic combination of the NK cell receptor KIR3DL1 and its weaker ligand HLA Bw4 80(T) was associated with spontaneous clearance of HCV infection in two independent cohorts. Further functional characterization showed that KIR3DL1 positive NK cells from patients with that HLA-Bw4 80(T) genetic background showed superior functionality. Besides the analysis of NK cells, HCV cohort studies helped to characterize the impact of an immune cell type that bridges the innate and the adaptive immune system, namely natural killer T cells, in HCV infection outcome. We could demonstrate that NKT cells are activated in chronically infected individuals, possibly driven by the cytokine milieu in these patients. The functional consequence is currently under further investigation. Even though HCV cure rates are nearly at 100%, HCV still poses a major healthcare problem, since infection could not yet be prevented. Immunological basic research could help to gain a better understanding of the causes that lead to spontaneous resolution or even which mechanisms protect individuals from infection. This knowledge could help to develop an HCV vaccination, which is needed for the global eradication of HCV.