Background We determine the optimal HCV treatment prioritization strategy for interferon-free HCV direct-acting antivirals(IFN-free DAAs) by disease stage and risk status incorporating treatment of people who inject drugs(PWID). Methods A dynamic HCV transmission and progression model compares the cost-effectiveness of treating patients early versus delaying until cirrhosis for patients with mild or moderate fibrosis where PWID chronic HCV prevalence is 20, 40 or 60%. Treatment is 12 weeks, ??3300/wk, 95% sustained viral response, varied by genotype/stage in alternative scenarios. We estimate long-term health costs(in ??UK=???1.3=$1.5) and outcomes as quality adjusted life-years gained(QALYs) using a ??20,000 willingness-to-pay per QALY threshold. We rank strategies with Net Monetary Benefit(NMB); negative NMB implies delay treatment. Results The most cost-effective group to treat were PWID with moderate fibrosis(mean NMB per early treatment ??60,640/??23,968 at 20%/40% chronic prevalence, respectively), followed by PWID with mild fibrosis(NMB ??59,258 and ??19,421, respectively) then ex-PWID/non-PWID with moderate fibrosis(NMB ??9,404). Treatment of ex-PWID/non-PWID with mild fibrosis could be delayed(NMB -??3,650). In populations with 60% chronic HCV among PWID it is only cost-effective to prioritize DAAs to ex-PWID/non-PWID with moderate fibrosis. For every one PWID in the 20% chronic HCV setting, 2 new HCV infections are averted. One extra HCV-related death is averted per 13 people with moderate disease treated. Rankings were unchanged with reduced drug costs or varied SVR/duration by genotype/fibrosis stage. Conclusions Treating PWID with moderate or mild HCV with IFN-free DAAs is cost-effective compared to delay until cirrhosis, except when chronic HCV prevalence and reinfection risk is very high.