For the High-Pressure High-Temperature (HPHT) pipelines susceptible to global buckling, a reasonable risk assessment is particularly significant for their safe operation and structural integrity. The complex physical and mechanical characteristics of deep-sea sediments could bring great uncertainty to the pipe-soil interaction and the corresponding lateral buckling predictions. In this study, the physical and mechanical characteristics of undisturbed sediment samples recovered from certain deep-water locations of South China Sea are analyzed statistically, which exhibit inherent natural variability. Such statistical variability can be well quantified with the Coefficient of Variation (COV). Results indicate that the COV of mechanical properties is generally more pronounced than that of physical properties. The probability distributions of most soil parameters generally follow normal distributions by statistical hypothesis testing. Reliability analysis for the pipeline lateral buckling is then performed on the basis of analytical models by Hobbs (1984) etc. The pipe-soil friction coefficient is described by a random variable with an appropriate type of probability distribution to reflect the randomness of pipe-soil interaction. Monte Carlo simulations indicate that the probability for pipeline lateral buckling could be up to 50% compared to the deterministic method. Moreover, the COV values of the critical safe temperature, the corresponding buckle length and buckle amplitude are closely related to, but smaller than that of the basic random variable. In comparison with deterministic analyses, the present analyses may provide a beneficial insight into the lateral buckling of HPHT pipelines by considering the statistical characteristics of deep-sea sediments.