To compare scleral lenses (SLs) with a quadrant-specific (study lens) or a spherical (habitual lens) landing zone in a crossover study. Seven participants (eight eyes) wore each of two lenses for 2 weeks before measurements. We measured visual acuity, contrast sensitivity, intraocular pressure (IOP), fluid reservoir clearance, corneal thickness, tear exchange, and lens experience. Variables were compared between lenses and before and after 2 hr of wear. The visual acuity was not different between the study lens, 0.12 logarithm of the minimum angle of resolution (logMAR), and habitual lens, 0.18 logMAR (median, P = 1.0). Contrast sensitivity was 1.3% under the study lens and 1.6% under the habitual lens ( P = 0.94). IOP did not change after 2 hr of wear for either lens (study lens, P = 0.33 and habitual lens, P = 0.74), and corneal thickness did not change during wear of either lens ( P = 0.44). The fluorescein concentration under the study lens did not change after 2 hr (99% of initial concentration; P = 0.84) but decreased to 46% of initial concentration under the habitual lens ( P = 0.008). Lens comfort was slightly better with the study lens (5.0 vs. 4.0, respectively; P = 0.05). SLs with spherical or quadrant-specific landing zones provide good vision and do not affect IOP or corneal thickness. However, tear exchange is greater under spherical lenses than under quadrant-specific lenses. The quadrant-specific lens provides greater patient comfort.