BACKGROUND AND OBJECTIVES: In order to provide a direct comparison of the effects of mode-locked systems to those with continuous-wave (CW) or nonpulsed output, we have performed an experiment with lasers possessing otherwise identical output characteristics. This in vivo minimum visible lesion study compares retinal effects of mode-locked and CW lasers complete with histopathology of the treated areas. STUDY DESIGN/MATERIALS AND METHODS: Titanium:Sapphire lasers produced 800-nm output for either mode-locked (76 MHz repetition rate, 120 femtoseconds) or CW exposures. Alternating CW and mode-locked laser exposures were delivered to the paramacular retinal region of rhesus subjects. Laser exposure duration was set to one-quarter second for both types of exposures. Through ophthalmoscopic examination of the fundus, a minimal visible lesion (MVL) threshold for damage was established. RESULTS: Approximately 75 test sites for each type of exposure were examined. The laser dosage thresholds and 95% confidence intervals for minimal visible damage at 24 hours postexposure were found to be 5.9 mJ (5.23-6.6 mJ) and 5.84 mJ (5.23-6.58 mJ) for mode-locked and CW exposures, respectively. CONCLUSIONS: Results are compared with published studies conducted at similar exposures. These nearly identical damage thresholds indicate a primarily thermal tissue damage mechanism. Comparative histopathology of acute and chronic lesions of both exposure types is also presented.