Objective: The study of effective factors on the quality of life (QoL), as an important criterion, in the outcome of new therapeutic and preventive strategies in human immunodeficiency virus (HIV) has been considered by researchers. To study the relationship between spiritual well-being and Health-Related Quality of Life (HRQoL) and some related factors in patients with Acquired Immunodeficiency Syndrome ([AIDS]/HIV). Methods: In this cross-sectional study, 224 people were selected as the study population (112 were male and 112 were female) from patients with AIDS/HIV at the Behavioral Counseling Center of Shiraz with available sampling method. The research tool was Palutzian & Ellison well-being scale and QoL Questionnaire (SF-36). Data were analyzed using Pearson correlation test. Results: There was a significant direct relationship between physical function dimensions (P = 0.003). There was a significant relationship between general well-being, mental well-being, and total spiritual well-being (P < 0.001). There was a statistically significant relationship between the dimensions of QoL and spiritual well-being with some age section of the patients, and their occupation and education (P < 0.001). Conclusions: Spirituality has an impact on the QoL dimensions. Therefore, HIV positive people\'s quality of life could be improved by the possibility of the spiritual well-being promotion as a method of adaptation with the disease.