Patients may be symptomatic, resulting in lower quality of life (QOL), despite L-thyroxine (LT4) therapy for hypothyroidism or having normal thyroid function. We hypothesized that their clinical symptoms of hypothyroidism and co-morbidities were associated with QOL. The study aimed to determine the association between the hypothyroid-related symptoms of Asian patients on LT4 treatment, their co-morbidities and their QOL. A questionnaire survey was conducted from November 2015 to July 2016 on consecutive multi-ethnic Asian patients on LT4 treatment for their hypothyroidism in a public primary care clinic in Singapore. Data on their demography, clinical symptoms, morbidity status, QOL scores based on the EQ5D instrument and thyroid function tests were computed and analysed, including logistic regression analysis to identify factors associated with lower QOL. Complete data of 226 Asian patients (79.0% women; 74.2% Chinese, 10.0% Malay, 13.1% Indian and 2.6% other minority groups; median age 57 years; 27.5% had previous thyroid surgery) were analysed. Their QOL was not associated with their socio-demographic profiles, clinical parameters and latest thyroid-stimulating hormone and free thyroxine levels. Patients reporting weight gain, dry or coarse skin, leg swelling, feeling weak and carpal tunnel syndrome had significantly lower QOL; 53.6% of them with any single symptom had lower QOL. More patients had lower QOL if they had two or more symptoms and multiple medical conditions. In Asian patients with hypothyroidism, weight gain, feeling tired, feeling weak, having dry or coarse skin, leg swelling and increased number of co-morbidities and symptoms were significantly associated with poorer QOL.