This article aims to explore the relationship between quality of life (QOL) and health-related behaviours among rural and metropolitan injecting drug users (IDU) using a new scale developed specifically for use with IDU.One-hundred and sixty-four rural and 96 metropolitan IDU from seven different NSW Area Health Services were interviewed using a cross-sectional survey, including the Injection Drug Use Quality of Life (IDUQOL) scale. The mean domain-based IDUQOL score was 59.4 (SD 22.3). The life areas most commonly selected by participants as important in determining their QOL were family, health, money, housing and partnerships. Rural participants were less likely to choose housing compared to those from the metropolitan areas, but were more likely to select independence. Rural participants also gave a lower mean rating to money (33.1 vs. 47.0) and to partnerships (53.8 vs. 71.1), suggesting differences in the composition of QOL among rural and metropolitan IDU. Compared to metropolitan participants, rural participants had a lower domain-based QOL score (56.1 vs. 64.5). No association was found between QOL and health-related behaviours such as drug use or sexual and injecting practices. IDU subjective assessment of QOL is mediated by a range of factors. Disparity between rural and metropolitan IDU appears to be influenced by non-health related areas such as partnerships and money, highlighting the need for a more holistic approach to the management of substance use problems.