Hyperreactive malarial splenomegaly (HMS), a common cause of massive splenomegaly in malaria-endemic regions, is defined as persistent splenomegaly without demonstrable underlying disease. Previous studies have found HMS more frequently in certain tribes in Papua New Guinea, Uganda and Nigeria, with strong familial associations in Uganda and Papua New Guinea. This case-controt study aimed to determine the extent of familial association of splenomegaly and the pattern of segregation of the condition in families in Ghana. It involved 22 HMS cases with 99 relatives, and 15 population controls of similar socio-economic background with 51 relatives. The pedigree of each family was recorded. Clinical and laboratory data were collected on all participants, including the presence and degree of spienomegaly. Relatives with splenomegaly were identified for 27% of HMS cases and for 6.7% of population controls (P=0.04). There were significant differences in the IgM levels, which were higher (P = 0.005), and the haemoglobin levels, which were lower (P = 0.009), in cases compared with controls. In Ghana, relatives of HMS cases are more likely to have splenomegaly than population controls, but with no obvious pattern of Mendelian segregation. HMS aetiology in Ghana is likely to be complex, involving multiple genetic and environmental factors. (c) 2005 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.