AbstractLiterature values vary widely for within‐subject test–retest reproducibility of gamma‐aminobutyric acid (GABA) measured with edited magnetic resonance spectroscopy (MRS). Reasons for this variation remain unclear. Here, we tested whether three acquisition parameters—(1) sequence complexity (two‐experiment MEscher–GArwood Point RESolved Spectroscopy [MEGA‐PRESS] vs. four‐experiment Hadamard Encoding and Reconstruction of MEGA‐Edited Spectroscopy [HERMES]); (2) editing pulse duration (14 vs. 20 ms); and (3) scanner frequency drift (interleaved water referencing [IWR] turned ON vs. OFF)—and two linear combination modeling variations—(1) three different coedited macromolecule models (called “1to1GABA”, “1to1GABAsoft”, and “3to2MM” in the Osprey software package); and (2) 0.55‐ versus 0.4‐ppm spline baseline knot spacing—affected the within‐subject coefficient of variation of GABA + macromolecules (GABA+). We collected edited MRS data from the dorsal anterior cingulate cortex from 20 participants (mean age: 30.8 ± 9.5 years; 10 males). Test and retest scans were separated by removing the participant from the scanner for 5–10 min. Each acquisition consisted of two MEGA‐PRESS and two HERMES sequences with editing pulse durations of 14 and 20 ms (referred to here as MEGA‐14, MEGA‐20, HERMES‐14, and HERMES‐20; all TE = 80 ms, 224 averages). We identified the best test–retest reproducibility following postprocessing with a composite model of the 0.9‐ and 3‐ppm macromolecules (“3to2MM”); this model performed particularly well for the HERMES data. Furthermore, sparser (0.55‐ compared with 0.4‐ppm) spline baseline knot spacing yielded generally better test–retest reproducibility for GABA+. Replicating our prior results, linear combination modeling in Osprey compared with simple peak fitting in Gannet resulted in substantially better test–retest reproducibility. However, reproducibility did not consistently differ for MEGA‐PRESS compared with HERMES, for 14‐ compared with 20‐ms editing pulses, or for IWR‐ON versus IWR‐OFF. These results highlight the importance of model selection for edited MRS studies of GABA+, particularly for clinical studies that focus on individual patient differences in GABA+ or changes following an intervention.