Serum cholinesterase (CHE) has been reported to be a significant indicator of liver function and prognosis in patients with cirrhosis. On the other hand, liver complications are frequent following allogeneic stem cell transplantation (HSCT). We therefore tested whether CHE was predictive of graft-versus-host disease and outcome in HSCT recipients. We studied 689 patients receiving a HSCT from an HLA-identical sibling (SIB) (n = 511), an alternative donor (n = 173) or a syngeneic twin (n = 5). Acute graft-versus-host disease (GVHD) was scored as 0-I, II, III-IV in 325 (47%), 279 (41%), and 85 patients (12%) respectively; 190 (28%) patients died of transplant-related complications (TRM). On day -7 the median CHE serum level was comparable in patients who either survived or died of TRM (5900 IU/l). On day 0, serum CHE levels were respectively 2310 and 2120 IU/l (P = NS) indicating the impact of the conditioning regimen. On day +7 after HSCT, the median level for surviving patients was 2598 IU/l vs 2309 IU/l for patients who subsequently died (P = 0.0002), on day +21 CHE levels were respectively 3348 vs 2528 IU/l (P < 0.00001), on day +50, 3575 vs 2358 IU/l (P < 0.00001) and on day +100 4193 vs 2729 IU/l (P < 0.00001). CHE levels on day +50 strongly correlated with aGVHD (3803 vs 3070 vs 1933 IU/l for patients with GVHD grade 0-I, II, and III-IV, respectively (P < 0.00001) and relapse (3569 for patients relapsing vs 3115 IU/l for patients not relapsing, P = 0.0006). In conclusion, (1) serum cholinesterase is a simple and reliable marker of acute GVHD and transplant-related complications; and (2) high CHE levels on day +50 predict relapse. If confirmed, the latter patients may be eligible for early reduction of immunosuppressive therapy.