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Simple Summary: In swine, the diagnosis of enteric diseases is challenging due to simultaneous presence of one or more microbic agents sharing similar clinical signs and pathological lesions. Therefore, the study of microscopic lesions is crucial in establishing the role of pathogens as causative agents in cases of co-infections; this can be confirmed by demonstrating agent–lesion co-localization. Although PCR is more sensitive than IHC, the latter provides a positive result only when the amount of antigen is significant, and therefore is likely the cause of the enteric pathology. Lawsonia intracellularis is the aetiologic agent responsible for Porcine proliferative enteropathy. However, it is complex to determine whether this intracellular bacterium is the cause of clinical disease due to its high prevalence in the field. In this study, we investigate the agreement between PCR and IHC results for L. intracellularis evaluation, and the infection and co-infection by porcine circovirus type 2 and L. intracellularis in the ilea of pigs presented with suspected proliferative enteropathy in Italy. The objective of this study was to employ a diagnostic algorithm, which involves detecting positive farms by stool PCR followed by PCR and histology/immunohistochemistry on ileum samples, for diagnosing Lawsonia intracellularis proliferative enteritis in Northern Italy. The primary aim was to examine the relationship between the gold standard of L. intracellularis diagnostics, namely histology and immunohistochemistry, and PCR in acute and chronic cases of L. intracellularis enteritides. An additional goal was to investigate the coinfection of L. intracellularis with porcine circovirus type 2 (PCV2). Twenty-eight ileum samples, including four from acute cases and 24 from chronic cases, were collected. PCR yielded positive results in 19 cases (four acute and 15 chronic cases). In comparison, immunohistochemistry was positive in 16 cases (four acute and 12 chronic cases), with an observed agreement of 89%. The findings suggest that performing the two tests in series can increase the specificity of the causal diagnosis. PCR may be used as a screening tool to identify the presence of the microorganism, and only positive cases will be examined by histology and immunohistochemistry to confirm the causative role of L. intracellularis. Co-infection with PCV2 was demonstrate in two out of four acute cases and in two out of 24 chronic cases, providing further evidence to support the hypothesis that when the infection starts with ubiquitous pathogens such as L. intracellularis, it may boost the possibility of PCV2 replication, especially in acute cases. As a result, this may trigger a transition from subclinical to clinical forms of PCV2 disease. [ABSTRACT FROM AUTHOR]