Objectives: HIV and sickle cell disease (SCD) are significant causes of morbidity and mortality in sub-Saharan Africa. Given their separate roles in immune dysregulation, our objective was to characterise the impact that SCD has on the presentation and progression of paediatric HIV. Methods: The study was a retrospective cohort study (study period 2004–2018). Cases of HIV + and SCD-afflicted patients (HIV+/SCD+) were obtained via electronic chart review from a paediatric HIV clinic in Kampala, Uganda and matched 1:3 with HIV + controls without SCD (HIV+/SCD-). Results: Thirty-five HIV+/SCD + subjects and 95 HIV+/SCD- controls were analysed (39% female (51/130), age 3.6 years (SD3.9)). At baseline, WHO clinical stage (64% total cohort Stage III/IV) and nutritional status (9.4% severe acute malnutrition) were similar for both groups, whereas HIV+/SCD + had higher though non-significant baseline CD4 count (1036 (SD713) vs 849 (SD638) cells/microlitre, P = 0.20, two-tailed t-test). There were 19 deaths, 6 (17%) HIV+/SCD + and 13 (14%) HIV+/SCD-, with unadjusted/adjusted models showing no significant difference. Nutritional progression and clinical stage progression showed no significant differences between groups. Kaplan–Meier analysis showed a slower rate of treatment failures in the HIV+/SCD + cohort (P = 0.11, log-rank survival test). Trajectory analysis showed that in the time period analysed, the HIV+/SCD + cohort showed a more rapid rise and higher total CD4 count (P = 0.012, regression analysis). Conclusion: The study suggests that SCD does not adversely affect the progression of HIV in patients on ART. Further, HIV+/SCD + achieved higher CD4 counts and fewer HIV treatment failures, suggesting physiological effects due to SCD might mitigate HIV progression.