Sperm parameters are known to be impaired in men with sickle cell disease (SCD). Although treatment with hydroxyurea (HU) impacts sperm quality, sperm preservation is impossible before puberty. The present study's primary objective was to analyze and compare sperm parameters in male SCD patients exposed (or not) to HU before puberty. Twenty-six sperm samples from 15 patients (median (range) age: 17 (16-23)) treated with HU during childhood were compared with 46 samples from 23 HU-naïve patients (median (range) age: 20 (16-24)). The median (range) age at HU initiation was 6 years (1-14), the median duration of HU treatment was 4 years (0.5-10) and the mean ± standard deviation dose of HU was 22.4 ± 3.7 mg/kg/day. Although we observed substantial quantitative and qualitative semen abnormalities in all patients, there were no significant differences in semen volume, sperm concentration, total sperm count, and spermatozoa motility, morphology and vitality between the HU-exposed and HU-naïve groups. At the time of the semen analysis, respectively 100% and 52% of the patients in the HU-exposed and HU-naïve groups were on transfusion therapy. Hydroxyurea's specific effect on spermatogenesis in very young infants and the putative value of transfusion for reversing HU's toxicity warrant further investigation.