Speckled antinuclear factor reacting with rat liver nuclei was found in a high proportion of sera from apparently healthy inhabitants of Western Nigeria, Northern Nigeria, Liberia and Uganda. A significant relationship was found between the occurrence of the antibody in Nigerian sera and the presence of high levels of malaria antibody and of high levels of IgM. Speckled antinuclear factor was also found in the sera of CBA mice infected with Plasmodium berghei. These findings suggest that the speckled antinuclear factor found in African sera may be a cross-reacting antibody to a nuclear component of malaria parasites. The demonstration of speckled antinuclear factor in the serum of a subject who has been resident in part of tropical Africa cannot be taken as a reliable indication of the presence of a connective tissue disease.