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To determine the minimal optical coherence tomography B-scan density for reliable detection of intraretinal and subretinal fluid.Spectral domain optical coherence tomography raster scanning (Spectralis; Heidelberg Engineering, Heidelberg, Germany) using a scan field of 20° × 20° of 97 B-scans with an interscan distance (ISD) of 60 μm was performed in 150 eyes of 150 consecutive patients at monitoring visits for intravitreal anti–vascular endothelial growth factor therapy. Using custom software, every other B-scan was repeatedly deleted to generate additional data sets with an ISD of 120 μm (49 B-scans), 240 μm (25 B-scans), and 480 μm (13 B-scans). Two independent reviewers evaluated the data sets for the presence of cystoid spaces of intraretinal fluid and subretinal fluid.Treatment diagnoses were neovascular age-related macular degeneration (68.0%), macular edema secondary to retinal vein occlusion (20.7%), diabetic macular edema (10.7%), and other retinal diseases (4.0%). Using the source data sets with an ISD of 60 μm, intraretinal fluid was detected in 56.0%, subretinal fluid in 19.3%, and either/both in 68.7%. Compared with these results, the sensitivity of detection of intraretinal fluid and/or subretinal fluid using an ISD of 120 μm, 240 μm, and 480 μm was 99.0% (95% confidence interval, 94.7–100.0; P = 0.5), 97.1% (91.7–99.4; P = 0.1), and 87.4% (79.4–93.1; P = 0.0001), respectively.An increase of ISD up to 240 μm does not significantly impair the detection of treatment-relevant exudative retinal changes in monitoring during intravitreal therapy of macular diseases. These findings are relevant for the choice of optical coherence tomography B-scan density in both routine clinical care and interventional clinical studies.