In this study, the damaging influence of excessive axle loading, tire inflation pressure and seasonal variation in climatic condition on the performance of flexible pavement in developing countries was analyzed by using the data from Pakistan as a case study. The Mechanistic-Empirical (M-E) design framework; based on GAMES (General Analysis of Multi-layered Elastic Systems) has been used for the analysis. Results were presented in terms of Relative Damage Factors (RDFs). Based on the analysis of results it was found that the performance of flexible pavements is sensitive to not only axle loading but also significantly to tire inflation pressure; a phenomenon common to many developing countries. The damaging influence of increase in tire pressure keeps on magnifying with each axle load increment. The Design RDF for the legal axle load (118 kN) and the mean observed axle load (145 kN) on single axle with dual tires; with mean observed tire pressure of 896 kPa, was noted to be 5.80 and 11.95, respectively. Consideration of climate regime in the design affects the economy of pavement design. The damage factors derived in this study can be readily used for network level pavement management.