This study was to determine the quality of life (QoL) and general mental health of subjects with leprosy compared with that of the subjects with albinism, and to evaluate the sociodemographic factors contributing to mental illness and impaired QoL among them. A total of 200 subjects were recruited for the study, 100 subjects with albinism and 100 participants with leprosy. The subjects with albinism were recruited from The Albino Foundation (TAF) in Enugu State, whereas the subjects with leprosy were recruited from the Mile Four Hospital, Abakaliki, Ebonyi State, both in South East Nigeria. In the first stage, a sociodemographic questionnaire was used to assess their sociodemographic characteristics, GHQ-28 and WHOQOLBref were also used to assess for caseness and quality of life respectively. In the second stage the GHQ positive cases and 10% of GHQ non-cases were interviewed with Mini International Neuropsychiatric Inventory (MINI), for specific ICD-10 diagnoses (psychiatric morbidity). The prevalence of psychiatric morbidity among the subjects with leprosy was 55%, while it was 41% among the subjects with albinism. The development of psychiatric morbidity was likely among subjects with leprosy if they were males or attended lower education, while it was likely in subjects with albinism who were females or single. The prevalence of psychiatric disorders among the subjects with leprosy were as follows: Depression 49.0%, GAD 18.2%, and Alcohol/Drug abuse 16.4%, whereas in the subjects with albinism group they were as follows: Depression 51.2%, GAD 26.8%, and Alcohol/Drug abuse 7.3%. The subjects with leprosy had significantly lower mean quality of life scores than the subjects with albinism in all the domains. In both groups those with psychiatric morbidity had significantly lower mean QoL scores in all the domains than those without psychiatric morbidity. The findings from this study have shown that mental illness and impaired quality of life may co-occur in subjects with albinism as well as participants with leprosy. It was more so among the subjects with leprosy than the subjects with albinism. Mental illness may lead to impaired quality of life. Impaired quality of life may also lead to mental illness. Programs to improve QoL and mental health are needed for subjects with albinism and participants with leprosy