Introduction Hepatitis C viral infection (HCV) remains one of the main causes of chronic liver disease worldwide. It has now become a curable disease due to the development of direct acting antivirals (DAA). Therefore, the WHO has set a target to eliminate HCV completely. To reach this target, people who inject drugs (PWID) need to be treated as they are the largest risk group for HCV in the Western world. Furthermore, treatment of HCV in PWID is recommended by the treatment guidelines. The aim was to study the uptake and outcome of treatment for HCV in PWID and the general population. Method We performed a Belgian, nation-wide, retrospective cohort study in 12 hospitals. All patients who were treated in these hospitals with simeprevir-sofosbuvir, daclatasvir-sofosbuvir, or ombitasvir/paritaprevir ritonavir - dasabuvir between December 2013 and November 2015 were included. These regimens were chosen based on the Belgian reimbursement criteria. All centers were experienced in treating HCV infected PWID. In case antiviral treatment was started, data were collected in a central database. PWID were subdivided in active users, defined by drug use during therapy with DAA, and former PWID. A PWID was defined by someone who used intravenous drugs at least once. Results The study population consisted of 419 patients: 111 PWID, subdivided in 23 active users and 88 former PWID, and 308 non-PWID treated with one of the above DAA regimens ± ribavirin. PWID (active and former) were younger (p=0.001), predominantly male (p=0.001), had a lower BMI (p=0.006), abused more alcohol (p=0.001), used more benzodiazepines (p=0.001) and were more infected with genotype 1a, 3 and 4 (p=0.001). Active PWID were less treatment experienced (p=0.05) and used less comedications (p=0.043). There were no differences in fibrosis score (F3, F4) (p=0.454) between all groups. PWID had a similar rate of side-effects (p=0.961). There was a trend towards more psychological complaints in PWID (p=0.051). Similar rates of treatment completion (p=0.095) and SVR (p=0.372) were achieved irrespective of active substance abuse. Conclusion Although DAA are safe and effective also in (active) drug users, PWID are still highly underrepresented in a Belgian treatment cohort, even the era of new DAA therapy. As this risk-group is at the heart of the HCV epidemic, more efforts are necessary to reach this group.