Poor acute pain control and inflammation are important risk factors for Persistent Postsurgical Pain (PPSP). The aim of the study is to investigate, in the context of a prospective cohort of patients undergoing hernia repair, potential risk factors for PPSP. Data about BMI, anxious-depressive disorders, neutrophil-tolymphocyte ratio (NLR), proinflammatory medical comorbidities were collected. An analysis for correlation between comorbidities and PPSP was performed in those patients experiencing chronic pain at 3 months after surgery. Tramadol resulted less effective in pain at movement in patients with a proinflammatory status. Preoperative hypertension and NLR > 4 were correlated with PPSP intensity. Regional anesthesia was significantly protective on PPSP when associated with ketorolac. Patients with pain at 1 month were significantly more prone to develop PPSP at 3 months. NSAIDs or weak opioids are equally effective on acute pain and on PPSP development after IHR, but Ketorolac has better profile in patients with inflammatory background or undergoing regional anesthesia. Drug choice should be based on their potential side effects, patient’s profile (comorbidities, preoperative inflammation, and hypertension), and type of anesthesia. Close monitoring is necessary to early detect pain conditions more prone to progress to a chronic syndrome.