OBJECTIVES: To estimate the net health benefits of intravitreal VEGF inhibitors indicated for patients with NV-AMD with differing baseline risks for cardiovascular events. METHODS: A decision-analytic risk-benefit model with a 10-year horizon was developed to jointly assess the intended and unintended effects of pegaptanib and of ranibizumab. Input data were abstracted from the results of published randomized controlled trials comparing active comparator to usual care (UC). Intended effects of treatment were quantified using the relative risk (RR) of progression to legal blindness (<20/200 visual acuity [VA]) in the better seeing eye. Unintended effects included key Anti-Platelet Trialists' Collaborative events (APTC: fatal or non-fatal myocardial infarction, cerebrovascular accident, or death from unknown or vascular cause) or severe non-ocular hemorrhages (NOH). Ranibizumab treatment was associated with RRs of 0.27 (progression to legal blindness; 95% confidence interval: 0.21-0.36), 2.2 (APTC events; 0.78-6.30) and 5.5 (severe NOH; 0.7-46.3). Pegaptanib was associated with RRs of 0.65 (progression to legal blindness; 0.54-0.79), 1.5 (APTC events; 0.4-5.3) and 0.8 (severe NOH; 0.2-3.0). Using utilities from the literature, net health benefits were calculated for 5%, 10%, 15% and 20% 10-year background risks of cardiovascular events. RESULTS: The estimated net health benefits for progression to legal blindness for both medications versus UC were positive and declined with increasing baseline risk of cardiovascular events. The absolute decline in benefit was greater for ranibizumab than for pegaptanib (0.67 vs 0.10 quality adjusted life years, respectively) when the background risk of APTC events increased from 5% to 20%. CONCLUSION: As it incorporates both intended and unintended effects, estimating net health benefits may be more informative than combining estimates of efficacy with an unstructured incorporation of adverse event rates. While both pegaptanib and ranibizumab show positive net health benefits for AMD, the risk of cardiovascular events is an important consideration when selecting treatment.