PURPOSE: To determine whether longitudinal changes in mesopic visual function on microperimetry occurred independent of its associations with microstructural parameters on spectral-domain optical coherence tomography (SD-OCT) in the early stages of AMD. METHODS: Forty-one AMD eyes underwent microperimetry testing and SD-OCT scans over a 12-month period at 6-month intervals. Microstructural parameters analyzed include the retinal pigment epithelium-drusen complex (RPEDC) layer thickness, number of hyperreflective foci (HF) and their inner retinal migration (represented by a weighted axial distribution score; AxD), and the number of atrophic areas. RESULTS: Microperimetric sensitivity was 0.29 dB (95% confidence interval [CI] = -0.38 to -0.20 dB, P < 0.001) and 0.13 dB (95% CI = -0.22 to -0.03 dB, P = 0.008) lower in each sector for every 10-μm higher RPEDC layer thickness and 1-HF present, but was not associated with the AxD score or the number of atrophic areas present (P ≤ 0.464). However, each 10-μm greater RPEDC layer thickness and 1-HF present was not independently associated with a further decline in sensitivity (-0.08 dB/year, 95% CI = -0.24 to 0.07 dB/year, P = 0.288 and 0.09 dB/year, 95% CI = -0.06 to 0.24 dB/year, P = 0.242, respectively) over time when accounting for the association between RPEDC layer thickness and number of HF with microperimetric sensitivity. CONCLUSIONS: Longitudinal changes in mesopic visual function measured on microperimetry paralleled changes in the microstructural changes over a 12-month time frame, without any changes occurring independent of the associations between structure and function alone.