Introduction: Although several studies have indicated that substance use disorders (SUD) adversely affect several domains of life such as health, economic wellbeing, living status and relationship with the law, there is paucity of studies focusing on the relationship of this condition with the individual’s subjective quality of life (QOL) in Nigeria. Objective: The objective of this study was to compare the subjective QOL of patients with SUD with those of patients with DM and the general population. Methodology: This study took place at the outpatient clinic of Federal Neuro-Psychiatric Hospital, Yaba (FNPH), for the SUD; the medical outpatient clinic of Lagos State University Teaching Hospital, Ikeja, (LASUTH), for DM; while the general population was sampled from the Lagos Mainland Local Government secretariat (LMLG). A sample of 140 subjects in each of the comparison groups was used to test the hypothesis of this study. QOL was assessed using the 26-item version of the WHOQOL instrument (WHOQOL-Bref). While subjects with SUD and DM were recruited on the basis of the managing consultants’ diagnoses, the subjects with DM and GPS were also assessed for general psychic distress and substance use disorder using GHQ-12 and WHO-CIDI instruments respectively. Participants included in the DM and the GPS were those with no SUD and with GHQ score less than 3. This study has a cross-sectional design. The SUD and the matched DM subjects were consecutive attendees at the respective outpatient clinics, while the general population subjects were chosen from the nominal roll of the LG to match the patients by age, gender and educational attainment. Data were analyzed using the SPSS version 17 and ANOVA used to compare the QOL in the 3 groups.