The aim of this study was to investigate whether lymphocyte vaccination can prevent diabetes occurring in the non-obese diabetic (NOD) mouse, an animal model of human insulin-dependent diabetes mellitus (IDDM). The lymphocyte vaccine was composed of lymphocytes isolated from the spleens of diabetic NOD mice, activated in vitro using concanavalin A (Con A) and rendered immunogenic using glutaraldehyde treatment. These cells were used to vaccinate mice at 6 weeks with boosters at weeks 10, 14 and 18. The animals were then monitored for signs of diabetes until week 30. Twenty-eight NOD mice (11 male, 17 female) were T-lymphocyte vaccinated while 35 littermates (14 male, 21 female) were sham vaccinated with the vaccine carrier, as control mice. The percentage of mice remaining non-diabetic was 50% in the T-lymphocyte-vaccinated group compared with 20% in control mice (P < 0.05). When the results were divided according to sex of the mouse the percentage of female NOD mice remaining non-diabetic was 47.1% in the T-lymphocyte-vaccinated group compared to only 9.4% in the controls (P < 0.01), while in the males there was no significant difference between the groups. These results suggest that T-lymphocyte vaccination can prevent diabetes in NOD mice and that it has its greatest effect in females. The therapy is apparently safe and its efficacy indicates that it may be of value in prediabetes in man.