Long-term effects of drug type and other drug use related risk factors on CD4+ cell decline were assessed in 224 HIV-infected injecting drug users (IDUs) from Baltimore (ALIVE), USA, and 63 IDUs from Amsterdam, The Netherlands. Higher frequencies of borrowing used injection equipment since 1980 resulted in a higher CD4+ count already present before seroconversion (P = 0.049). Use of mainly heroin in the seroconversion interval resulted in a sharper CD4+ decline until the first 6 months after seroconversion (P = 0.004), but CD4+ values converged later on. This finding might reconcile earlier discordant epidemiological and laboratory study results regarding the possible effects of heroin.