Deficiencies in complement components are rare diseases whose diagnosis is often underestimated. In addition, in only a few cases molecular studies have been carried out for the characterization of the underlying genetic defects. To date, studies involving C5-deficient patients are scarce. The aim of the present report is to characterize the biochemical and molecular complement deficiency in two non-related families with one or more members showing no detectable hemolytic complement activity (CH50<50 U/ml) and reporting a history of several episodes of meningitis. Protein deficiency was assessed by means of hemolytic assays, bi-dimensional double immunodiffusion, ELISA and Western blot of patients' sera. Molecular studies were carried out by PCR and RT-PCR of DNA and RNA, respectively, both extracted from fresh blood samples of each family member. In Family A, only the propositus had complete C5 deficiency. Molecular studies showed that he was heterozygous for two changes in the C5 gene. One of the mutations was also carried by the father (c.1883_1884AG<CTCT) and the second (c.2536T>C, Y846H) was a de novo mutation. In Family B, the two C5-deficient members share the homozygous nonsense mutation c.892C>T (Q298X) in exon 9. The characterization of these new mutations is interesting in order to elucidate structure-function relationships in the C5 gene and it also helps to understand the molecular basis of this uncommon deficiency. Moreover, this report highlights the importance of complement screening in cases of repeated meningococcal infections in order to establish its involvement and to consider adequate clinical recommendations such as prophylactic antibiotics or meningococcal vaccines.