We have examined the immunosuppressive effects of combined azathioprine (Aza) and ciclosporin (CS) in two groups of mongrel dogs receiving kidney allografts. In group 1 Aza and CS were given together daily after transplantation and in group 2 twice the dose of each drug was given separately on alternate days. Doses were halved in each group at successive 84-day intervals and all immunosuppression was stopped on day 336. Thus the same total amounts of Aza and CS were given to all recipients in both groups. Up to day-60 the incidence of rejection in each group was similar, thereafter recipients in group 1 were more susceptible to fatal infection and marrow hypoplasia. This accounted for the difference in long-term survival between the two groups (1/14 in group 1, 5/12 in group 2 at day 420). Subsequently, two long-term survivors in group 2 died, 1 on day 452 from chronic rejection and the other on day 529 from gastroenteritis with a histologically normal allograft kidney. An in vitro analysis of the alloreactive repertoire of two healthy recipients in group 2, bearing each other’s kidneys for more than 2.5 years and more than 500 days without immunosuppression, showed a profound donor-specific defect which could account for their operationally tolerant stat