OBJECTIVE To illustrate 2 common problems encountered in evaluating the response of cytomegalovirus retinitis to antiviral treatment and to consider their clinical importance. METHODS Four illustrative cases were selected from 76 cases reviewed during a study that compared clinical evaluation and centralized grading of fundus photographs in the assessment of cytomegalovirus retinitis. RESULTS These cases illustrate 2 problems noted during the review: (1) that progression of retinitis may be difficult to recognize clinically in the absence of an obvious increase in retinitis border activity and (2) that movement of retinitis borders by 750 microns or more (the principal criterion used to define retinitis progression) during the initial 4 weeks of treatment does not necessarily represent an unfavorable response to treatment. CONCLUSIONS Ophthalmologists who participate in the management of cytomegalovirus retinitis should be aware of the subtlety of retinitis activity that sometimes accompanies progression in patients undergoing treatment with currently approved agents. Side-by-side comparison of good-quality photographs from the current visit (as soon as they are available) with photographs from previous visits, using adequate illumination and magnification, may be helpful in detecting progression promptly. When applying the results of clinical trials to clinical practice, clinicians should not equate retinitis border movement of 750 microns or more during the first 4 weeks of treatment with treatment failure.