Objectives: The role of injury-related variables in determining health-related quality of life (HRQOL) among Iranian persons with spinal cord injury (SCI) has not yet been fully described. In this study, we compared HRQOL between individuals with injury at cervical level and those with injury at thoracolumbar sections and evaluated the discriminating value of injury level as a determinant of HRQOL among Iranian people with SCI. Methods: Individuals with SCI, who were referred to Brain and Spinal Cord Injury Research Center, were invited to participate in this investigation. HRQOL was assessed using the Short Form (SF-36) questionnaire to determine the quality of life (QOL) in eight domains: physical functioning (PF), role limitation due to physical problems (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role limitation due to emotional problems (RE), and mental health (MH). Results: Ninety patients with paraplegia and 94 quadriplegic patients participated in this investigation. The mean score of PF domain was significantly lower in patients with injury at cervical level (p < 0.0001). There was no significant difference in other domains of SF-36 between subjects with paraplegia and quadriplegia (p = 0.670, 0.700, 0.910, 0.710, 0.730, 0.290 and 0.850 for RP, RE, VT, MH, SF, BP and GH, respectively). Similarly, the mean physical component summary (PCS) score was significantly higher among individuals with injury at thoracolumbar sections (p < 0.0001). The mean mental component summary (MCS) score did not differ between the two groups (p = 0.720). Conclusions: Patients with SCI at the cervical level have similar mental health compared to those with injury at thoracolumbar sections, which shows proper mental adaptability in quadriplegic individuals. Injury level can be used as a major determinant of the physical component of QOL among people with SCI.