Many hyperplasias and lymphomas of marginal zone B-cells are associated with infection. We identified 6 children and 1 adolescent with cervical lymphadenopathy showing a prominent polyclonal nodal marginal zone hyperplasia (pNMZH) and 4 adolescents with monoclonal paediatric nodal marginal zone lymphoma (pNMZL). The clonality status was assessed using BIOMED 2-IG PCR analysis. H. influenzae was identified in all 6 pNMZH that could be tested by direct culture (N = 3) or a very sensitive PCR for the H. influenzae gyrase gene in frozen materials (N = 5). H. influenzae was not detected in 3 pNMZL and 28 non-specific reactive cervical lymph nodes of age-matched controls, except for a single control node that was obtained during oropharyngeal surgery for a cleft palate showing very low copy numbers of H. influenzae. pNMZH patients were younger than pNMZL patients (median age 12 versus 21 yr). pNMZH showed a prominent nodular appearance with variable fibrosis without acute inflammation. Within the nodules the expanded germinal centres and variably sized marginal zones were colonized by activated B cells with weak expression of IgD and lack of CD10 and/or BCL6 expression. Some areas showed skewed light chain expression in plasma cells (4/5 cases lambda). In 4 cases tested this was confirmed by flow cytometry for surface Ig (3/4 cases lambda). In contrast, pNMZL showed more extensive expansion of marginal zones by centrocytoid cells and often expression of BCL2 protein. Several H. influenzae strains are known to interact with the constant part of IgD on human B-cells, leading to their polyclonal proliferation and activation. We speculate that in vivo stimulation of IgD(+) marginal zone B-cells by this bacterium may be implicated in this particular lymphadenopathy that should be distinguished from monoclonal pNMZL.