Background Cement film space plays a significant role in achieving good adaptation of indirect restorations. The objective of this study is to investigate the effect of cement space parameters on the marginal adaptation of computer-aided design (CAD)/computer-assisted manufacturing (CAM) endocrowns. Methodology The coronal part of 10 freshly extracted human mandibular molars was reduced to a level of 1.5 mm above the cementoenamel junction (CEJ); then, root canal treatment was performed. On each tooth, four lithium disilicate endocrowns with different cement space parameters (40, 80, 120, and 160 µm) were designed and fabricated using CAD/CAM. Endocrowns were seated to their prepared teeth, and the vertical marginal gap was measured in 20 equidistant points for each endocrown using a stereomicroscope on 90× magnification. The mean marginal gaps of the four groups were compared using a one-way analysis of variance (ANOVA) and the Tukey honestly significant difference (HSD) test considering p<0.05 as the cutoff for statistical significance. Results The mean marginal gap of the 40 µm, 80 µm, 120 µm, and 160 µm groups were 46.25±21.20 µm, 21.75±11.10 µm, 15.94±06.62 µm, and 13.10±07.08 µm, respectively. One-way ANOVA showed a significant difference in the marginal gaps between groups (p<0.001). The Tukey post hoc test showed a statistically significant mean difference between 40 µm and each of the other three groups (p<0.001). Conclusion The cement space parameter variation affects the marginal adaptation of endocrowns. The cement space of 40 µm resulted in a higher marginal gap than cement spaces of 80, 120, and 160 µm.