Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50 years) and 82 younger (<50 years) HIV-infected adults were administered a measure of PM in the laboratory and subsequently were monitored for ARV adherence for 30 days using the Medication Event Monitoring System. In the older group, better time-based PM performance was associated with higher likelihood of adherence, irrespective of pill burden. Within the younger sample, time-based PM was positively related to adherence only in participants with lower pill burdens. Younger HIV-infected individuals with higher pill burdens may overcome the normal effects of time-based PM on adherence through compensatory medication-taking strategies, whereas suboptimal use of these strategies by younger HIV-infected individuals with lower pill burdens may heighten their risk of ARV nonadherence secondary to deficits in time-based PM.