Objectives/Hypothesis To study and compare the outcome of trans-oral CO2 laser microsurgery for early glottic squamous cell cancer with and without the involvement of anterior commissure (AC). Study Design This is a retrospective analysis of 296 cases of early glottic squamous cancer treated by trans-oral CO2 laser microsurgery. Methods The patients were divided into two groups depending on whether AC was involved or not. The impact of AC involvement on rates of local recurrence, laryngeal preservation, overall survival, and disease-specific survival was compared in both the groups. Results Out of the 296 cases, 61 cases had AC involvement, while in 235 cases AC was free of disease. Local recurrence rate was significantly higher at 29.51% in the group with AC involvement, while only 18.3% cases had local recurrence in the group without AC involvement with P value of 0.0001. On T stage-wise analysis, 34.8% cases of T2 lesions with AC involvement developed local recurrence, as compared to only 10.26% cases of T2 without AC involvement with significant P value of 0.007. Larynx preservation rate was 95.8% versus 93.26% in the AC-involved and AC not-involved cases, respectively, without any statistical significance (P=0.287). The overall survival was 90.16% versus 86.38% in the cases with and without AC involvement, respectively, without significant P value 0.642. Conclusions Trans-oral laser surgery is an excellent treatment option in patients with early glottic cancer irrespective of whether or not the AC is involved. Trans-oral laser microsurgery for early glottic cancer involving AC requires adequate exposure, proper assessment, good experience, and advanced surgical skills.