Tolerance develops in a proportion of long-term liver transplant recipients but currently cannot be identified before an attempt at withdrawal from immunosuppression therapy. In the present study, we have examined the immunophenotypic characteristics of the cellular infiltrate in portal tracts and lobules as observed in liver biopsy specimens in relation to the outcome of subsequent withdrawal from immunosuppression therapy. Cryostat biopsy specimens from 27 long-term recipients before drug withdrawal, and from 10 patients with recent transplants who were having acute rejection, were analyzed. Immunohistochemical staining was performed for CD3+ (pan T cell), CD8+ (cytotoxic), CD4+ (helper), CD45RO+ (memory), CD45RA+ (naive), CD56+ (natural killer), CD68+ (macrophage), and CD8+ perforin+ cells. Fewer CD8+ and CD3+ cells were present in the lobular areas of biopsy specimens from patients who were successfully withdrawn from immunosuppression therapy (n = 6) compared with biopsy specimens from patients with nontolerant grafts (n = 9; 15 vs. 23 cells/high-power field [hpf] [P < .01] and 16 vs. 26 cells/hpf [P < .03], respectively) or biopsy specimens obtained during acute rejection (15 vs. 31 cells/hpf [P < .01] and 16 vs. 32 cells/hpf [P < .01]). Cell frequencies in the biopsy specimens of nontolerant long-term patients were similar to those found with acute rejection. Immunophenotyping the lobular inflammation within long-term liver allografts assists in identifying those patients in whom drug withdrawal is likely to be unsuccessful and in whom it is postulated a form of inactive, latent cellular rejection exists.