In an urban and a rural area of Guinea-Bissau, the incidence of and mortality due to measles were followed over four years. Significantly higher case-fatality ratios among secondary cases occurred when infection was transmitted across sexes than within the same sex. The case-fatality ratio was highest for girls infected by boys and lowest for girls infected by girls. Published reports of cases of fatal measles indicate a similar tendency. Apparently, no general background factor or difference in social interaction between children can explain this variation in severity of infection. It is therefore hypothesized that cross-sex transmission of measles virus produces infections of greater severity. These observations may suggest that measles virus incorporates host-specific cellular characteristics that interfere with the immune responses of persons infected by a member of the opposite sex.