Scale‐up of HIV services in countries such as Uganda has resulted in a rapid increase in facilities offering antiretrovirals (ARVs) and an increase in healthcare workers trained to deliver care. Consequently, evaluating medication safety is increasingly important in these settings. Data from developed countries suggest that drug‐drug interactions (DDIs) involving ARVs are common, occurring at rates of 14–58%. Few data are available from low resource settings, however a study of 996 Kenyan patients found that 33.5% were at risk of clinically significant DDIs. We evaluated the prevalence and type of ARV DDIs and the patients most at risk in an African outpatient setting. A random sample of patients taking current ARVs and accessing care at the Infectious Diseases Institute, Makerere University, Kampala was selected from the clinic database. The most recent prescription for each patient was screened for DDIs using www.hiv‐druginteractions.org. Clinical significance of DDIs was assessed by two of us using a previously developed technique evaluating: likelihood of interaction, therapeutic index of affected drug and severity of potential adverse effect. From 1000 consecutive patients 99.6% were taking≥1 co‐medication alongside their ARV regimen (mean 1.89). 24.5% had≥1 potential DDI, with a total of 335 DDIs observed. Of these, 255 DDIs were considered clinically significant, affecting 18.8% of patients. Only 0.3% of DDIs involved a contraindicated combination. There was a higher rate of potential DDIs observed in patients taking TB treatment (p=0.0047), who were WHO stage 3 or 4 (p=0.001), or patients taking ≥2 co‐medications alongside ARVs (p<0.0001) (Fishers exact test). Patient age, gender, CD4 count and weight did not affect risk for DDIs. Co‐medications commonly associated with potential DDIs were antibiotics (6.2% of 1000 patients), anthelminthics (4.6%) and antifungals (3.5%). Potential DDIs involving ARVs occur at similar rates in resource‐limited settings and developed countries. Drug combinations which most frequently cause DDIs, however, differ between settings; for example CNS and cardiovascular drugs in the UK and anti‐infectives in Kenya and Uganda. Development of tools which are relevant to particular settings are essential for recognition of DDIs. Initiatives such as incorporation of WHO essential medicines into the Liverpool DDI database and the AIDS Treatment Information Centre in Uganda are important in achieving this.