The number of HIV-1-infected patients harboring multidrug-resistant viruses is increasing. Since new antiretroviral drugs with favorable resistance profiles are limited, innovative strategies are urgently needed. Treatment interruptions can lead to a loss in HIV resistance followed by improved response to reinitiated therapy. The authors report the case of a patient with sustained antiretroviral response for 3.5 years after a 7-month treatment interruption. Concomitant with an increase in replication capacity, multidrug-resistant viruses gradually disappeared during treatment interruption. Resistance to protease inhibitors (PI) was completely lost, and resistance to reverse transcriptase inhibitors was still present when therapy was reinitiated. PI-resistant variants were not detected at four time points after treatment reinitiation. The alignment of the nucleic acid sequences from all different time points suggested that the viruses obtained after treatment reinitiation evolved from less-resistant variants prior to treatment interruption. This was supported by in vitro propagation of the viral plasma population and an individual clone derived from the time point of treatment interruption. This is consistent with a model favoring reversible binding of HIV-1 to reservoirs, as has recently been proposed for follicular dendritic cells. Understanding of this process could help to exploit the reduced fitness of drug-resistant viruses for treatment interruptions.