Objective: Depression is highly prevalent yet under diagnosed and undertreated among patients with chronic hepatitis C virus (HCV) infection. Collaborative care models have improved depression outcomes in primary care settings, and this study aimed to provide more information on testing such methods in specialty HCV care. Methods: Hepatitis C Translating Initiatives for Depression Into Effective Solutions (HEPTIDES) was a randomized controlled trial that tested a collaborative depression care model in HCV clinics at four Veterans Affairs facilities. The HEPTIDES intervention consisted of an offsite depression care team (depression care manager, pharmacist, and psychiatrist) that delivered collaborative care. Participant interview data were collected at baseline and at six months. The outcome was depression severity measured with the Hopkins Symptom Checklist (SCL-20) and reported as treatment response (≥50% decrease in SCL-20 item score), remission (mean SCL-20 item score <.5), and depression free days (DFDs). Results: Baseline screening identified 263 HCV-infected patients with depression. In unadjusted analyses, intervention participants' reports trended toward more treatment response (19% versus 13%) and remission (12% versus 6%), but total number of DFDs (50.9) was similar to that of usual care participants (50.7). These trends did not reach statistical significance for the overall sample in the adjusted analyses: response (odds ratio [OR]=2.02, 95% confidence interval [CI]=.98-4.20), remission (OR=2.63, CI=1.00-6.94), and DFDs (β=7.6 days, CI=-.99 to 16.2). However, the intervention was effective in improving all three outcomes for patients who did not meet criteria for remission at baseline (SCL-20 score >.5, N=245). Conclusions: Depression collaborative care resulted in modest improvements in HCV patient depression outcomes. Future research should investigate intervention modifications to improve outcomes in specialty HCV clinics.