Managing patients who present late with HIV infection is challenging. All late-presenting patients should have an individual treatment plan that encompasses both antiretroviral therapy and, where necessary, treatment for opportunistic diseases. Timely initiation of treatment in late presenters is crucial but the optimal time to start therapy depends on many individual factors, including the presence of opportunistic infection and potential drug-drug interactions. Primary drug resistance is an important contributor to poor clinical outcomes in HIV; resistance profiling before treatment initiation is therefore recommended. The choice of initial HIV treatment should reflect patient characteristics, the results of resistance testing and the complexity of concomitant disease.