OBJECTIVES: Evaluate cost effectiveness of ocriplasmin single intravitreal injection for the treatment of symptomatic vitreomacular adhesion (sVMA; called vitreomacular traction) with or without (±) full-thickness macular hole (FTMH) ≤400µm compared with standard of care (SOC; watchful waiting followed by vitrectomy, if clinically needed), based on the current United States (US) clinical practice and payer perspective. METHODS: A state-transition (partitioned vision distribution) model was designed to simulate patient transitions between health states over time. Cost per quality-adjusted life-year (QALY) gained was estimated over a lifetime and short-term (2-year) horizon. Analyses were stratified by FTMH at baseline. Clinical efficacy parameters were sourced from the Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) study, a Phase 3b, randomized, 24-month clinical trial. Health care costs reflected direct medical costs paid by the federal government. RESULTS: In patients with sVMA ±FTMH ≤400µm, ocriplasmin treatment generated additional QALYs (8.34 vs 7.98) at an increased cost ($6,193 vs $4,295) compared with SOC at the lifetime horizon. The lifetime incremental cost-effectiveness ratio (ICER) was $5,358 per QALY gained. The probability of being cost-effective was 97.9% at the US willingness-to-pay threshold of $50,000 per QALY. In patients with isolated sVMA, ocriplasmin treatment generated additional QALYs (8.42 vs 7.95) at an increased cost ($4,480 vs $2,275) with a lifetime ICER of $4,685 per QALY gained. The probability of being cost-effective was 96.7% at the $50,000 per QALY threshold. In patients with sVMA +FTMH ≤400µm, ocriplasmin treatment generated additional QALYs (8.18 vs 8.06) at an increased cost ($9,439 vs $8,126) with a lifetime ICER of $10,986 per QALY gained. The probability of being cost-effective was 79.5% at the $50,000 per QALY threshold. CONCLUSIONS: In the US, ocriplasmin is cost-effective and produces health-related quality of life benefits compared with SOC for patients with sVMA ±FTMH ≤400µm.