The effects of different in vivo thymosin alpha one (T alpha 1) treatments on T-cell responses inhibited by cocaine abuse were studied. Administration during cocaine treatment promoted a faster recovery of normal natural killer (NK) cell activity after the suspension of abuse. Suspension of cocaine plus repeated T alpha 1 administrations strongly restored NK activity and, interestingly, spleen cells from mice treated with T alpha 1 during and after cocaine administration achieved a very rapid recovery and the greatest stimulation of natural cytotoxicity. This last treatment also restored the cocaine-inhibited specific T-cell response (i.e. allogeneic cytotoxic T-lymphocyte (CTL) generation) and abrogated the cocaine-induced suppression of interferon gamma (IFN-gamma), interleukin 2 (IL-2) and IL-4 production. Finally restoration and induction of thymic cellularity were significant when T alpha 1 was given during and after cocaine administration. The present investigation provides evidence for the first time that thymic hormones could be of potential value in controlling cocaine-induced impairment of T-cell-mediated immunity in the mouse.