Posterior lumbar interbody fusion (PLIF) surgery represents an effective option to treat degenerative conditions in the lumbar spine. To reduce the drawbacks of the classical technique, we developed a variant, so-called Lateral-PLIF, which we then evaluated through a prospective consecutive series of patients. All adult patients treated at our institute with single or double level Lateral-PLIF for lumbar degenerative disease from January to December 2017 were prospectively collected. Exclusion criteria were patients < 18years of age, traumatic patients, active infection, or malignancy, as well as unavailability of clinical and/or radiological follow-up data. The technique consists of insert the cages bilaterally through the transition zone between the central canal and the intervertebral foramen, just above the lateral recess. Pre- and postoperative (2years) questionnaires and phone interviews (4years) assessed pain and functional outcomes. Data related to the surgical procedure, postoperative complications, and radiological findings (1year) were collected. One hundred four patients were selected for the final analysis. The median age was 58years and primary symptoms were mechanical back pain (100, 96.1%) and/or radicular pain (73, 70.2%). We found a high fusion rate (95%). A statistically significant improvement in functional outcome was also noted (ODI p < 0.001, Roland-Morris score p < 0.001). Walking distance increased from 812m ± 543m to 3443m ± 712m (p < 0.001). Complications included dural tear (6.7%), infection/wound dehiscence (4.8%), and instrument failure (1.9%) but no neurological deterioration. Lateral-PLIF is a safe and effective technique for lumbar interbody fusion and may be considered for further comparative study validation with other techniques before extensive use to treat lumbar degenerative disease.