Carbohydrate-binding agents (CBAs) like the plant lectins HHA (Hippeastrum hybrid agglutinin) and UDA (Urtica dioica agglutinin), but also the non-peptidic antibiotic pradimicin A (PRM-A) inhibit entry of human immunodeficiency virus (HIV) into its target cells by binding to the glycans of gp120. Given the high sequence identity and similarity between the envelope gp120 glycoproteins of HIV and simian immunodeficiency virus (SIV), the inhibitory activity of a variety of CBAs were evaluated against HIV-1, HIV-2 and SIV. There appeared to be a close correlation for the inhibitory potential of CBAs against HIV-1, HIV-2 and SIV replication in cell culture and syncytia formation in co-cultures of persistently SIV-infected HUT-78 cell cultures and uninfected CEM cells. CBAs also inhibit transmission of the SIV to T-lymphocytes after capture of the virus by DC-SIGN-expressing cells. A total of 8 different SIV strains were isolated after prolonged HHA, UDA and PRM-A exposure in virus-infected cell cultures. Each virus isolate consistently contained at least 2 or 3 glycan deletions in its gp120 envelope and showed decreased sensitivity to the CBAs and cross-resistance towards all CBAs. Our data revealed that CBAs afford SIV and HIV-1 inhibition in a similar manner regarding prevention of virus infection, DC-SIGN-directed virus capture-related transmission, and selection of drug-resistant mutant virus strains. Therefore, SIVmac251-infected monkeys might represent a relevant animal model to study the efficacy of CBAs in vivo.