Introduction: Drug misuse has been identified as a significant problem in homeless populations. This study examines aspects of physical and mental health, perceived quality of life and health service use among homeless illicit drug users and compares these to non-drug users. Methods: Participants were recruited through health clinics across Dublin. A questionnaire assessed participants’ drug use, health and well-being, health behaviours and use of health services. Descriptive statistics are presented for the entire cohort and drug users separately. Logistic regression analysis was used to examine the relationship between drug use and (i) multimorbidity,(ii) anxiety and/or depression, (iii) perceived quality of life and (iv) use of health services. Results: Of 105 participants recruited, 35 (33%) were current drug users. Current and previous drug users were significantly more likely to have multimorbidity than those who had never taken drugs (OR 4.86, 95% CI 1.00–23.66). There was no significant difference between drug users and non-drug users in the prevalence of anxiety and/or depression. Drug users were five times more likely than non-drug users to have a low perceived quality of life (OR 5.2, 95% CI 1.7–16.0). Health service utilization was high, although some services were used less by drug users (e.g., dentist and psychiatric outpatient services) while others were used more often (e.g., phoneline services and day care centres). Conclusion: This study highlights the high levels of drug use in this population and the negative impact of drug use on health and perceived quality of life of a homeless population in Dublin.