Bauer, D. J., L. St. Vincent, C H. Kempe (Univ. of Colorado Medical Center, Denver, Col. 80220), P. A. Young and A W. Downie. Prophylaxis of smallpox with methisazone. Amer. J. Epid., 1969, 90: 130–145.—A trial of the prophylactic effect of methisazone against smallpox was carried out among the close contacts of smallpox patients admitted to the Infectious Diseases Hospital, Tondiarpet, Madras, in 1963. Treatment with methisazone was begun 1–2 days after admission of the patient to hospital. A similar number of contacts were kept under observation without being given treatment. The number of cases of smallpox which occurred among the two groups of contacts during an observation period of 14–16 days was recorded. Among 2,610 contacts who were treated, there were 18 cases of smallpox (0.69%) with four deaths, compared with 113 cases (4.17%) with 21 deaths among 2,710 who were not treated. The reduction in incidence associated with treatment was significant (p < 0.001). The drug was given by mouth according to four dosage schedules. There were five cases among 1,137 contacts given a single dose of 3 g; none among 584 given two doses of 3 g with an interval of eight hours; one among 384 given 1½ g twice daily for four days; and none among 57 given 3 g twice daily for four days. The distributions of age and vaccination status, degree of exposure and other demographic criteria among these contacts did not differ significantly from those among the corresponding groups of untreated contacts except in the groups receiving one or two doses of 3 g. These groups contained a higher proportion of unvaccinated persons so that there was a slight bias against the success of treatment. The reduction in incidence could therefore be ascribed to the effect of treatment with methisazone. The high yield of cases among the untreated contacts, most of whom were vaccinated or revaccinated after contact, showed that vaccine alone was in no way fully effective in conferring protection when exposure had already occurred. The marked reduction in incidence when methisazone treatment was combined with vaccination of previously unvaccinated contacts shows that vaccine should be used in combination with chemoprophylaxis in order to obtain more effective control of an outbreak of smallpox.