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There is growing recognition of the influence of substance use, particularly alcohol use, on HIV disease progression. This study investigated how hazardous/harmful use of alcohol and drugs impacts the health status of 1503 patients attending HIV clinics. Of the sample, 37 % indicated hazardous/harmful drinking and 13 % indicated a drug problem. Hazardous/harmful use of alcohol and drugs was significantly related to health status, with participants using substances more likely to have TB-positive status (χ2 = 4.30, p < 0.05), less likely to be on ARVs (χ2 = 9.87, p < 0.05) and having lower CD4 counts (t = 4.01, p < 0.05). Structural equation modelling confirmed the centrality of hazardous/harmful use of alcohol as a direct and indirect determinant of disease progression. Based on these findings it is recommended that patients attending HIV clinics be routinely screened for problematic alcohol and/or drug use, with strong emphasis on ensuring ARV adherence in those with problematic alcohol use.