PURPOSE: To compare fluorescein leakage from choroidal neovascularization (CNV) with signs of intraretinal or subretinal fluid on time-domain optical coherence tomography (TD-OCT) and spectral-domain optical coherence tomography (SD-OCT) in patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy for CNV caused by age-related macular degeneration (AMD). DESIGN: Retrospective, consecutive case series. PARTICIPANTS: Fifty-nine eyes of 56 patients with neovascular AMD receiving anti-VEGF therapy. METHODS: All patients were imaged with fluorescein angiography (FA), TD-OCT (Stratus, Carl Zeiss Meditec, Inc., Dublin, CA), and SD-OCT (Cirrus, Carl Zeiss Meditec, Inc). All images were analyzed by an experienced reading center grader masked to all clinical data. Fluorescein leakage from CNV and OCT abnormalities (presence of interstitial fluid, retinal cystoid abnormalities, and subretinal fluid) were documented for each visit. MAIN OUTCOME MEASURES: Agreement of OCT findings with presence or absence of fluorescein leakage from CNV. RESULTS: For TD-OCT, the sensitivity, specificity, positive predictive value, and negative predicative value (and 95% confidence intervals) for OCT abnormalities were 59% (46-72), 63% (50-75%), 61% (49-73), and 61% (48-74), respectively. For SD-OCT, the sensitivity, specificity, positive predictive value, and negative predictive value (and 95% confidence intervals) for OCT abnormalities were 90% (82-98), 47% (34-60), 62% (49-75), and 82% (72-92), respectively. CONCLUSIONS: Spectral-domain optical coherence tomography seems more likely than TD-OCT to detect abnormalities when fluorescein leakage from CNV is detected after anti-VEGF therapy. However, SD-OCT also seems to detect abnormalities frequently in the absence of fluorescein leakage from CNV. Whether treatment decisions based on any of these modalities result in visual acuity outcomes that are similar or superior to monthly treatments without such evaluations is unknown, but this study provides information that may assist in the design of studies to evaluate the role of OCT and FA in the management of CNV. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.