A retrospective study on 235 natural cases of Porcine Respiratory Disease Complex in order to determine the etiological agents, their prevalence and interrelationships was performed in Serbia. Lung tissue samples were analyzed by Polymerase Chain Reaction for the presence of Porcine circovirus type 2, Porcine reproductive and respiratory virus, Swine influenza virus, Mycoplasma hyopneumoniae, Pasteurella multocida, Actinobacillus pleuropneumoniae, Haemophilus parasuis, Streptococcus suis and Arcanobacterium pyogenes. A total of 49 different combinations of viral and bacterial pathogens were found. Five different viral and viral/Mhp co-infections were detected. Monobacterial infections were found in 150 cases and polybacterial infection was detected in 85 samples. PCV2 was the main virus detected, and Pm was the most aggressive secondary pathogen detected in PRDC. The reason for PRDC being so prevalent among Serbian pigs is most likely due to the large number of risk factors in the conventional farrow-to-finish system, compared to multi-site production systems. Therefore, measures aimed at a better control of respiratory viruses, particularly Porcine circovirus type 2 and Porcine reproductive and respiratory virus, as well as Mycoplasma hyopneumoniae infections, and adoption of rational decisions on respiratory bacterial pathogens specific therapeutic and preventive strategies at herd level, simultaneously with significant improvements on farm management should reduce the occurrence of PRDC.