The direct results of these efforts were the conception, planning, and implementation of the Cryotherapy for ROP randomized clinical trial of cryotherapy against observation (no treatment). A group of ophthalmologists from the United States intimately involved in the development of knowledge of ROP and its classification, among them Earl Palmer, MD, the study's principal investigator, David Schafer, MD, Graham Quinn, MD, Dale Phelps, MD, myself, and others, put together the manual of procedure. In this effort, we were joined by Robert Hardy, PhD, professor of epidemiology and biostatistics at the School of Public Health, University of Texas, Houston, who lent design and biostatistical expertise and served as study coordinating center principal investigator during this and subsequent studies. The study manual of procedure outlined in exquisite detail every step in the selection of eligible infants, examining technique, diagnosis of the disease, threshold for treatment, technique of treatment, and follow-up of the infant's treated eye. Because the disease was most often symmetrical in patients (> 80%), one eye served as the treated eye and the other as its control. The threshold for treatment was greater than 5 clock hours of grade 3 ROP in zone 1 or 2 accompanied by plus disease—defined for the study as dilated and tortuous veins and arteries of the posterior pole vessels. Twenty-three centers were enrolled in the study and their principal investigators were trained in the study protocol, applying ICROP to the disease as they examined premature infants of birth weight less than 1251 g and accurately diagnosing ROP and its severity. After careful peer review, the National Eye Institute fully supported the study and subsequent follow-up of the enrolled infants. The study compared treatment with cryotherapy to the avascular retina for threshold ROP vs observation and no treatment for threshold disease in the opposite eye. Subjects were randomized by eye when the level of ROP was equal in both eyes and by patient when one eye was at the threshold but the other was not. Unfavorable outcome was defined as a total retinal detachment or a retinal fold through the macula destroying central vision. The results, both anatomical and later functional, were positive for cryotherapy. The finding of an unfavorable outcome in the treated eye was reduced by 50% (to approximately 25%) over its nontreated control (unfavorable outcome in approximately 46%). Some 291 premature infants were entered in the trial. At that point, the trial was stopped as it became clear that even if all future infants needed to attain sample size had failed cryotherapy, the study results would not be reversed. The infants enrolled in the study have been carefully followed up for 15 years. And although the visual results have not been as striking as had been hoped, they have nevertheless maintained a statistically significant edge over the results in the untreated eye. Cryotherapy proved to be far less successful in zone 1 disease than in zone 2 disease, where fortunately greater than 75% of the disease occurs. It is important to note that unfavorable outcomes as stage 5 (total retinal detachment) outnumbered stage 4B (a retinal fold extending through the macula) by a ratio of 13 to 1. The treated unfavorable results were far more common proportionately in zone 1 disease than in zone 2 disease.