In the past 30 years, great strides have been made in immunizing infants and children routinely in developing countries under the Expanded Programme on Immunization. Despite this, the introduction of Haemophilus influenzae type b (Hib) vaccines has progressed rather slowly compared to previously-introduced vaccines for infant immunizations. This slower uptake has been attributed partly to the need for data on the burden of invasive Hib disease. To understand this need, conceptual underpinnings and prerequisites were explored for Hib disease-burden studies. Methodological approaches were also reviewed for conducting Hib disease-burden studies that may be considered in developing countries. Potential studies span a range of designs that provide varying levels of clinical, laboratory and epidemiologic evidence of the burden of invasive Hib disease. Carefully-conducted studies can lay the foundation for complementary studies of long-term disability due to invasive Hib disease, national economic analysis, and field evaluations of vaccine. Studies done in collaboration with national agencies and clinical investigators will maximize study value and provide critical data for national decision-makers who make choices regarding the introduction of Hib vaccines.