PURPOSE: To systematically assess the ability to detect change and retest reliability for a panel of visual function assessments in ABCA4 retinopathy. DESIGN: Prospective natural history study (NCT01736293). METHODS: Patients with at least 1 documented pathogenic ABCA4 variant and a clinical phenotype consistent with ABCA4 retinopathy were recruited from a tertiary referral center. Participants underwent longitudinal, multifaceted functional testing, including measures of function at fixation (best-corrected visual acuity, low-vision Cambridge Color Test), macular function (microperimetry), and retina-wide function (full-field electroretinography [ERG]). Two- and 5-year ability to detect change was determined based on the $η$2 statistic. RESULTS: A total of 134 eyes from 67 participants with a mean follow-up of 3.65 years were included. In the 2-year interval, the microperimetry-derived perilesional sensitivity ($η$2 of 0.73 [0.53, 0.83]; -1.79 dB/y [-2.2, -1.37]) and mean sensitivity ($η$2 of 0.62 [0.38, 0.76]; -1.28 dB/y [-1.67, -0.89]) showed most change over time, but could only be recorded in 71.6% of the participants. In the 5-year interval, the dark-adapted ERG a- and b-wave amplitude showed marked change over time as well (eg, DA 30 a-wave amplitude with an $η$2 of 0.54 [0.34, 0.68]; -0.02 log10(µV)/y [-0.02, -0.01]). The genotype explained a large fraction of variability in the ERG-based age of disease initiation (adjusted R2 of 0.73) CONCLUSIONS: Microperimetry-based clinical outcome assessments were most sensitive to change but could only be acquired in a subset of participants. Across a 5-year interval, the ERG DA 30 a-wave amplitude was sensitive to disease progression, potentially allowing for more inclusive clinical trial designs encompassing the whole ABCA4 retinopathy spectrum.