PURPOSE: To characterize the natural history of rod-mediated dark adaptation (RMDA) over 2 years in eyes with intermediate age-related macular degeneration (AMD). This information will be useful in understanding the potential of RMDA to serve as a functional endpoint in proof-of-concept studies and clinical trials on intermediate AMD. METHODS: RMDA was measured in eyes with intermediate AMD at baseline and follow-up visits over 2 years at 6, 12, 18, and 24 months. A computerized dark adaptometer measured sensitivity for targets centered at 11° on the superior vertical meridian of the retina. Rod intercept time (RIT) characterized the speed of dark adaptation and was defined as the duration (in minutes) required for sensitivity to reach a criterion level of 3.0 log units of attenuation of the stimulus. RESULTS: Mean change in RIT over 24 months for 30 eyes was 10.5 minutes (standard deviation 19.4), p < 0.0001; 73.3% of eyes had a RIT increase >1 minute, 56.7% had an increase >3 minutes, and 36.7% had an increase >6 minutes; for 26.7% RIT was unchanged (0- to 1-minute increase) or decreased. Greater increase in RIT over 24 months was associated with smoking. CONCLUSIONS: RMDA slows in intermediate AMD over 2 years in most eyes. There was wide variability in RIT at both baseline and in the extent to which it increased over 24 months. A major risk factor for AMD, smoking, exacerbated RMDA slowing. TRANSLATIONAL RELEVANCE: RMDA as assessed by RIT may be useful as a functional endpoint in proof-of-concept studies and clinical trials on intermediate AMD with 2-year designs.