A high-speed railway (HSR) construction boom has been observed in China during the past few years, in which prestressed concrete (PSC) box-girders are widely used for HSR bridges. Concerns have been raised regarding the long-term deflection of girders under the combined actions of concrete creep, shrinkage, and tendon relaxation, since the time-variant deflection significantly undermines the safety of high-speed trains. This paper presents the time-variant deflection reliability analysis of an existing HSR PSC box-girder bridge, in which a hybrid method, consisting of the response surface (RS) method, the finite element (FE) method and the checking point method (i.e., the JC method), is used. The pre-and post-cracking behaviors of the thin-walled box girder are described by using composite degenerated shell elements with the smeared cracking model and the Hordijk's tension softening relation. In particular, the CEB-FIP model for creep and shrinkage is applied in the finite-element (FE) analyses. By using the probabilistic sensitivity analyses, random variables that significantly affect the time-variant deflection are selected for the reliability calculation. It is found that the deflection reliabilities are high in the early stage of bridge service but decrease rapidly during the first 10 to 20 service years. Higher speed limits result in a significant decrease in deflection reliability indices, which may fall below the target value prior to the expected service life. The proposed methodologies can be used in the design optimization, speed control and making rational maintenance or repair strategies for HSR PSC bridges.