Objective: The midline supracerebellar infratentorial (SCIT) approach and its paramedian development are commonly used for dealing with pineal lesions. Comparative clinical studies are lacking, however. We aim to establish the better performance of the paramedian SCIT approach in terms of clinical safety in surgically treated pineal cysts and pineal region tumors. Procedural functionality and effectiveness have been also analyzed. Methods: A comparative analysis of clinical, radiologic, pathologic, and surgical features, and outcome was performed between 55 midline and 57 paramedian SCIT approaches that were exclusively performed in 112 patients (57 pineal cysts and 55 tumors of the pineal region) operated in sitting position by a single surgeon. Information was retrieved from hospital records and microsurgical videos. Results: The paramedian SCIT approach linked with fewer postoperative complications (odds ratio [OR]: 0.40) and fewer approach-related complications (OR: 0.28) than the midline SCIT approach. The SCIT paramedian approach was achieved in a shorter time, by a smaller bone flap, and with fewer complex procedural steps than the midline approach. The SCIT paramedian approach did not require the opening of the falx cerebelli, midline cerebellar retraction, section of the midline cerebellar draining veins, nor wide opening of the dura. Gross total resection, size of the lesion, microsurgical time for removal, histopathological diagnosis and postoperative outcome were statistically similar in both groups. Conclusions: The SCIT approach represents a safer and more functional approach for the removal of cysts and tumors of the pineal region than the classic midline approach, while maintaining the same effectiveness.