BACKGROUND: Anxiety disorders frequently occur in people who inject drugs (PWID). This study aimed to explore changes in anxiety among PWID during and after treatment of hepatitis C virus (HCV) with direct-acting antiviral agents. METHODS: This study is a secondary analysis using a sample (N = 498) based on the per-protocol data from the HERO study, a multisite pragmatic randomized trial. Anxiety among PWID was measured using the 7-item Generalized Anxiety Disorders (GAD-7) scale. Linear mixed-effects models were used to analyze changes in anxiety across multiple timepoints (baseline and end-of-treatment follow-up weeks 12, 24, 48, 120, and 168) stratified by sustained virologic response (SVR) status, baseline anxiety categories, and baseline benzodiazepine use. RESULTS: Anxiety significantly decreased overall during the study period (p <
0.001) except at week 48. A significant reduction in anxiety was also observed among those with SVR (p <
0.05 at all time points from baseline), but not among those without SVR. The baseline anxiety categories differed significantly with respect to the changes in anxiety scores over the study period (p <
0.001). Reductions of anxiety scores from baseline were significantly lower at all timepoints for the moderate and severe anxiety categories. Anxiety scores were significantly greater among people who tested positive for benzodiazepines at baseline versus those negative at baseline at all later time points (p <
0.05) except at week 24. CONCLUSIONS: Following curative treatment of HCV in PWID, symptoms of generalized anxiety showed durable improvement through 168 weeks and among patients with moderate to severe anxiety. Those who used benzodiazepines at baseline showed elevated anxiety in the follow-up period.