Quality of life (QoL) is increasingly being recognized as an important outcome for rehabilitation programs, and has mainly been used to compare the efficacy of interventions or to compare amputees with other diseased populations. There is relatively a limited number of studies primarily focusing on analyzing the multitude of factors influencing QoL in amputees. To identify important background and amputation related factors which affect quality of life (QoL) in lower limb amputees, and to compare QoL profile of amputees' to that of general population. Cross-sectional. Lower limb amputees 18 years and above from a rehabilitation centre, a limb-fitting centre and four limb-fitting camps were interviewed (n = 605). Structured questionnaires included patient background and amputation characteristics, and the MOS short-form health survey (SF-36) for assessing QoL. The SF-36 was administered to a general adult population using purposive sampling (n = 184). SF-36 PCS and MCS scores were found to be significantly lower for amputees when compared to those for the general population. In this study, employment status, use of an assistive device, use of a prosthesis, comorbidities, phantom-limb pain and residual stump pain were found to predict both PCS and MCS scores significantly, and explained 47.8% and 29.7% of variance respectively. Age and time since amputation accounted for an additional 3% of variance in PCS scores. The abovementioned factors should be addressed in order to ensure holistic reintegration and participation, and to enable the amputees to regain or maintain QoL. Prospective longitudinal studies are recommended to systematically study the change in QoL over time and to assess its determinants. Proper appraisal of abovementioned factors in the rehabilitation programme would assist in establishing a treatment protocol, which would adequately address QoL in amputees.