OBJECTIVES: Given the importance of adherence to combination antiretroviral therapy (cART) for the reduced morbidity and improved mortality of people living with HIV infection (PLWH), we set out to determine which of a number of previously investigated personal, socioeconomic, treatment-related and disease-related factors were independently associated with self-reported difficulty taking antiretroviral therapy (ART) in an Australian sample of PLWH. METHODS: Using data from a national cross-sectional survey of 1106 PLWH, we conducted bivariate and multivariable analyses to assess the association of over 70 previously investigated factors with self-reported difficulty taking ART. Factors that maintained an association with reported difficulty taking ART at the level of α=0.05 in the multivariable logistic regression analysis were considered to be independently associated with reported difficulty taking ART. RESULTS: A total of 867 (78.4%) survey respondents were taking antiretroviral medication at the time of completing the HIV Futures 6 survey. Overall, 39.1% of these respondents reported difficulty taking ART. Factors found to be independently associated with reported difficulty taking ART included younger age, alcohol and party drug use, poor or fair self-reported health, diagnosis of a mental health condition, living in a regional centre, taking more than one ART dose per day, experiencing physical adverse events or health service discrimination, certain types of ART regimen and specific attitudes towards ART and HIV. CONCLUSIONS: Thirteen previously investigated factors were found to be independently associated with reported difficulty taking ART, reaffirming the dynamic nature of adherence behaviour and the ongoing importance of addressing adherence behaviour in the clinical management of PLWH.