Introduction Post-treatment Quality of Life (QOL) is considered an important outcome in cancer patients. A number of questionnaire tools have been designed for its assessment. University of Washington Quality of Life (UW QOL) questionnaire version four is a reliable tool for assessment of post-treatment QOL in oral squamous cell carcinoma (OSCC) patients. Our aim was to identify the post-treatment problems faced by OSCC patients and to assess the impact of clinical factors affecting post-treatment QOL by using UW QOL (version four) questionnaire. Methods The study was conducted on 59 patients with OSCC who were treated with curative intent at Patel Hospital, Karachi from August 2015 to September 2015. Patients were asked to fill the UW QOL questionnaire (version four) on their follow-up visit. Results Overall mean composite QOL score was 66.59 ± 16.98. Chewing and saliva (dryness of mouth) had the lowest scores (38.98 ± 37.2 and 56.78 ± 41.4, respectively) among all domains while pain and anxiety had the highest scores (80.93 ± 20.4 and 79.66 ± 29.8, respectively). Patients having tumors of the tongue, late stage (III and IV) tumors, and restricted mouth opening had significantly lower mean composite QOL scores. Patients with tongue tumors revealed significantly lower scores for pain, swallowing, mood, and anxiety. Patients with late-stage tumors showed significantly lower scores for chewing, swallowing, taste, saliva, appearance, anxiety, and recreation. Patients with restricted mouth opening had significantly lower scores for pain, speech, appearance, recreation, and anxiety domains. Conclusion Different clinical features have different impacts on QOL in terms of problems faced by the patients. Features having a significant effect should be identified, and measures focused on most relevant problems should be employed in order to improve the post-treatment QOL
