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Background: Sickle cell disease (SCD) is one of the most frequent and traumatizing genetic disease in Uganda, with the prevalence of the sickle cell trait (SCT) estimated at 13.3% leading to serious psycho-social and economic impact on the patients and their families., Aim: This study aimed to determine the burden of SCT and factors influencing the uptake of screening services among secondary school students in Uganda., Methods: We used an analytical cross-sectional design with a multi-stage sampling approach. A total of 399 students from four secondary schools in Kampala City were enrolled in this study. Data were gathered using semi-structured questionnaires and blood screening. We used the sickling test to determine the presence of sickle cell alleles among the participants and hemoglobin electrophoresis as a confirmatory test. Data gathered using the questionnaire were analyzed using descriptive and inferential statistics., Results: In total, 5.8% of participants who were tested during this study had SCT. Most (80.2%) participants were not in an intimate relationship at the time of data collection. The majority (60.4%) had moderate knowledge about SCT screening and obtained information about screening from the school. Only 29 (7.3%) participants knew of a family member with sickle cell. Overall, participants had a negative attitude toward SCT screening (67%), although 41.6% believed that most people who were sickle cell carriers did not live long and were often sick. Statistically significant associations were found between testing for SCT and knowing a partner's sickle cell status (odds ratio [OR] 2.112, p = 0.043) and Anglican religion (OR 2.075, p = 0.047)., Conclusion: Despite the moderate level of knowledge and negative attitudes, a relatively large number of participants had SCT. This highlights the need for a comprehensive health education package targeting adolescents to promote SCD/SCT screening., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Namukasa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)