Efficient approaches are needed for obtaining reliable insights into the safety, in developing and developed country settings, of interventions for prevention of mother-to-child transmission (MCT) of HIV. A randomized trial designed with an appropriate sample size and adequate duration of follow-up provides a powerful tool for obtaining causal evidence regarding the safety and efficacy of MTC prevention interventions. Such trials are ideal for detecting adverse effects (AEs) that occur in the short or moderate term and with moderate to high frequency. Passive and active surveillance procedures, where practical, can provide valuable insights regarding long-term or rare AEs. Ideally, surveillance procedures should be carefully planned sufficiently early to allow prospective definition and uniform collection of important classes of AEs, enhancing the sensitivity and specificity of these surveillance data.