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To examine treatment decisions by ophthalmologists versus reading center fluid identification from optical coherence tomography in Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Fluid in 6,210 optical coherence tomography scans (598 patients) in “as needed treatment” arm of CATT Year 1 was compared with ophthalmologist's treatment: positive fluid agreement (PFA, fluid+, treatment+) and positive fluid discrepancy (PFD, fluid+, treatment−), negative fluid agreement (fluid−, treatment−) and negative fluid discrepancy (fluid−, treatment+). For PFDs, fluid location and visual acuity were characterized.Treatment and reading center fluid determination agreed in 72.1% (53.0% PFA, 19.1% negative fluid agreement) and disagreed in 27.9% (25.7% PFD, 2.2% negative fluid discrepancy) of visits, with no discrepancies for 20.9% of patients. Compared with PFA, PFD occurred more commonly with lower total foveal thickness (mean ± SD: 265 ± 103 PFD, 366 ± 151 μm PFA), presence of intraretinal fluid only, smaller fluid areas (PFA areas greater than twice those of PFD, P < 0.001), and greater decrease in retinal and lesion thickness. Mean acuities before, at, and after PFD were 65.8, 66.9, and 66.3 letters.Treatment decisions by ophthalmologists matched reading center fluid determination in the majority of visits. More pronounced response to treatment and smaller foci of fluid likely contributed to PFD. Positive fluid discrepancy did not have substantial impact on subsequent visual acuity.