PURPOSE: To assess the longitudinal association between outer retinal microstructure and mesopic as well as scotopic retinal sensitivity in patients with drusen secondary to intermediate age-related macular degeneration (iAMD). DESIGN: Prospective, longitudinal natural history study. PARTICIPANTS: Fifty-nine eyes of 54 patients with large drusen (> 125 $μ$m) associated with iAMD and 27 age-matched healthy control eyes. METHODS: Participants underwent spectral-domain OCT and both mesopic and scotopic fundus-controlled perimetry (FCP). Annual follow-up visits were performed over a 3-year period. MAIN OUTCOME MEASURES: Pointwise correlation of retinal sensitivity stimuli to corresponding standardized (Z score) pointwise retinal thickness. Linear mixed-effect models were applied to analyze longitudinally the association of pointwise retinal thickness changes, follow-up time, or both with retinal function. RESULTS: At baseline, mean pointwise sensitivity in patients was reduced by -1.67 dB (95% confidence interval [CI], -2.22 to -1.12) for mesopic and by -2.34 dB (95% CI, -2.85 to -1.84) for scotopic testing compared with controls with a pointwise sensitivity change of -0.35 dB/year (95% CI, -0.43 to -0.28) for mesopic and +0.20 dB/year (95% CI, 0.12-0.29) for scotopic testing, respectively (P < 0.001). Retinal thickness analysis in patients revealed a significantly thinner outer nuclear layer (ONL) by -0.49 standard deviation (SD; 95% CI, -0.70 to -0.28 SD) and a significant thicker retinal pigment epithelium-drusen complex (RPEDC) by +3.22 SD (95% CI, 2.27-4.17 SD) at baseline, respectively (P < 0.001). During follow-up, retinal thickness thickened further by +0.51 SD/year (RPEDC) and thinned by -0.03 SD/year (ONL; P = 0.045) and -0.34 SD/year (inner and outer photoreceptor segments) in patients, respectively (P < 0.001). Structure-function analysis showed a significant association of the ONL and the RPEDC thickness change with both types of FCP sensitivity testing (P < 0.001). Besides, follow-up time had a significant (independent) effect on mesopic and scotopic retinal sensitivity (P < 0.001). CONCLUSIONS: The longitudinal structure-function correlation demonstrated a progressive quantifiable degeneration of the outer retina in iAMD associated with photoreceptor dysfunction. Because longitudinal sensitivity changes could not be explained by structural changes alone, an unmet need remains for additional refined parameters on retinal structure to predict retinal function.