Quality of Life (QoL) is a consistent and powerful predictor that affects the out-come in end-stage renal disease (ESRD) patients on dialysis. This study was undertaken to identify the factors that might predict QoL scores among ESRD patients on hemodialysis (HD). The study was conducted at three HD units in Saudi Arabia from January 2007 to January 2008. We studied 100 HD patients (53 males and 47 females) and used the SF-36 and KDQoL-SF forms covering six domains of QoL, namely physical, emotional, social, illness impact, medical and financial satisfaction, and overall general health. The mean age of the study patients was 47.5 ± 13.8 years and the mean duration of dialysis was 77.2 ± 75.5 months. The QoL scores were 45.8 ± 17.1 for general health, 53.1 ± 32.0 for physical QoL, 50.5 ± 14.8 for emotional QoL, 54.9 ± 18.1 for social QoL, 46.5 ± 13.7 for illness impact, and 45.9 ± 12.2 for the medical and financial domain. The total QoL score was 49.5 ± 13.7. The male patients had statistically significantly reduced QoL and younger patients had better QoL scores. The QoL scores revealed a decreasing trend with decreasing level of education; they were elevated among employed patients. Multiple linear regression analysis demonstrated that age, dialysis duration, and male sex were negative predictors of QoL score. We conclude from our study that QoL is reduced in all the health domains of HD patients. Older age, male gender, unemployment, and duration of dialysis adversely affected the QoL scores. Adequate management of some of these factors could influence patient outcomes.