Objective:To investigate the role of maternal HIV‐1 isolate phenotype and a child's cell susceptibility/resistance to viral infection in mother‐to‐child HIV‐1 transmission.Patients and methods:Forty‐nine women were studied at the time of delivery. Primary isolates, obtained by culturing patient peripheral blood mononuclear cells (PBMC) with PBMC from healthy donors, were characterized for tropism and syncytium‐inducing capability in monocyte‐derived macrophages (MDM), peripheral blood lymphocytes (PBL), and in the MT‐2 and MOLT‐3 T‐cell lines.Results:Seven women transmitted HIV‐1 to their children. Primary isolates were obtained from six and 28 transmitting and non‐transmitting mothers, respectively. All primary isolates from transmitting mothers and their infants but only 50% of those from non‐transmitting mothers replicated in MDM, regardless of their replication capacity in T‐cell lines. PBL and MDM cells from six uninfected children were exposed to the corresponding maternal isolates. Polymerase chain reaction analysis of HIV‐1 DNA in cells and p24 antigen assay in culture supernatants disclosed that two PBL and five MDM cultures were resistant to viral infection; two other PBL cultures, although HIV‐1‐infected, were negative for p24 production. Depletion of CD8+ cells only partially restored productive infection in CD4+ cell cultures. Moreover, all six PBL but only one MDM cultures were productively infected by an isolate obtained from a transmitting mother, thus suggesting that MDM resistance to HIV‐1 infection is not viral isolate‐restricted.Conclusions:Our findings strongly suggest that mother‐to‐child HIV‐1 transmission is influenced by both monocyte‐macrophage tropism of the maternal isolate and susceptibility of the child's target cells, in particular monocyte‐macrophages, to HIV‐1 infection.AIDS 1995,9:427‐434