Purpose: To evaluate the effects of long-standing early detection program in the incidence and trends of severe retinopathy of prematurity (ROP) in Cali, Colombia. Methods: This was a retrospective cohort study of infants included in an ROP prevention, early detection, and prompt treatment program, from January 01, 2002, to December 31, 2021 (20 years). Infants with gestational age (GA) <37 weeks or birth weight (BW) <2000 g and those with known ROP risk factors were screened. The incidence of severe ROP was calculated, and the average annual percent change (AAPC) was estimated through a joinpoint model. Results: 16,580 infants were screened, with an average GA and BW of 31.4 ± 2.8 weeks and 1526.5 ± 56.7 g, respectively. The incidence of severe ROP was 2.69% (446 cases, 95% confidence interval [95%CI]: 2.45%; 2.95%), with an average annual decrease of - 14% (AAPC, 95%CI: -16.3%; -11.6%) from 13.6% in 2002 to 0.7% in 2021. In infants with GA <32 weeks, the incidence was 5.21%. A significant reduction in the risk of ROP was observed with increasing GA and BW (P < 0.05). Among the cases with severe ROP, 6.5% (29/446) had a GA =32 weeks with a maximum of 37 weeks; only 0.4% (2/446) of the detected infants had a BW >2000 g. Conclusion: Awareness and screening as part of the early detection program to prevent ROP has shown a significant decline in the incidence of severe ROP over time. Screening infants with GA <32 weeks or BW <2000 g and preterm infants (<37 weeks) with risk factors may be a feasible decision for resource optimization. [ABSTRACT FROM AUTHOR]