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The health-related quality of life (HRQoL) for hemodialysis (HD) patients is typically lower than that of kidney transplant patients. Considering that HRQoL is significant for the treatment and well-being of HD patients, this study aimed to evaluate HRQoL among patients undergoing HD in Saudi Arabia. This is a cross-sectional study that was conducted at Dr Sulaiman Al-Habib Hospital in Riyadh, Saudi Arabia, between June and October 2025. Multivariable logistic regression analysis was performed to examine factors associated with physical and mental health outcomes. This study included 93 HD patients. Males had significantly higher PCS (65.72 ± 29.44) and MCS (72.01 ± 23.70) compared to females (PCS: 45.31 ± 29.75; MCS: 56.17 ± 27.18; P < .001). Educational level significantly differed with MCS (P = .02), with high school graduates and postgraduate degree holders having higher MCS scores. Employment status was also differed in both PCS (P < .001) and MCS (P = .02). Higher itching in the past 24 hours was associated with lower odds of both PCS (adjusted odds ratio (aOR) = 0.76, 95% confidence intervals [CI]: 0.61-0.96, P = .018) and MCS (aOR = 0.64, 95% CI: 0.48-0.85, P = .002). for mental health, being Saudi national (aOR = 0.05, 95% CI: 0.00-0.98, P = .048), having a high school education (aOR = 17.74, 95% CI: 1.99-158.18, P = .010), being a student (aOR = 0.01, 95% CI: 0.00-0.55, P = .024), spending 1 to 5 years (aOR = 0.18, 95% CI: 0.03-1.00, P = .050), were all associated with higher MCS scores. The current study revealed that males had significantly higher PCS and MCS than females. Hence, considering these findings is essential to developing efficacious targeted interventions to improve HRQoL among patients on HD, particularly those with lower PCS and/or MCS scores. Further studies are required to explain differences in PCS and/or MCS scores among certain patients' demographic groups.