All-trans-retinoic acid (RA) has been shown either to activate or repress human immunodeficiency virus type 1 (HIV-1) replication in primary monocyte-derived-macrophages (MDMs). We systematically investigated the contribution that cell donor and virus differences make to this variability. We found that the effect of RA was cell donor dependent. In addition, the ability of RA to repress HIV-1 replication varied between different virus stocks. In no case did RA affect either virus entry or integration but instead affected the accumulation of viral mRNAs in infected cells. Despite the complex variability in RA responsiveness in untreated cells, we found that RA consistently repressed virus replication when the MDMs were treated with concentrations of interleukin 1 beta (IL-1 beta) and IL-6 that are expected at local sites of infection, where HIV-1-infected macrophages reside in vivo.