AIM: To evaluate the effect of rigid gas permeable contact lens (RGP-CL) on corneal morphological parameters and vision-related quality of life in keratoconus (KC) patients. METHODS: Totally 57 eyes of 30 KC patients who were followed-up for more than two years, including 17 RGP wearers (32 eyes) and 13 non-wearers (25 eyes) were retrospectively analyzed. Initial medical history and corneal topography were collected at baseline. Corneal topography, corneal aberration, optical coherence tomography, and vision-related quality of life questionnaires were performed at the last follow-up. RESULTS: According to corneal topography, increase of the flattest keratometric values was higher in RGP wearers than in non-wearers (P=0.038). The morphological parameters, including symmetry index of front corneal curvature (P=0.004) and Baiocchi-Calossi-Versaci index front (P=0.047), were lower in RGP wearers than in non-wearers. Vertical coma was smaller in RGP wearers than non-wearers in 3.0, 5.0, 6.0, and 7.0 mm pupil diameters, respectively (P<0.05). The environmental triggering domain of ocular surface disease index was worse in RGP wearers as compared to non-wearers (P=0.003). At the last follow-up, there were no significant differences in constituent ratios of KC progression, corneal thickness topography, epithelial thickness topography, morphological parameters of corneal topography, and other questionnaire scores between the two groups (all P>0.05). CONCLUSION: Long-term use of RGP does not worsen KC but may cause corneal epithelial remodeling to increase symmetry of corneal anterior surface, reduce corneal vertical coma and improve visual quality. However, RGP wearing causes a slight decrease in vision-related quality of life. The occurrence of ocular surface symptoms is mainly associated with environmental triggering factors.