Objective: To investigate the effect of acupressure therapy as an adjunctive therapy to pharmacological treatment on pain and health-related quality of life (QOL) among knee osteoarthritis (KOA) patients.Methods: One hundred KOA patients were recruited from the orthopedic out-patient clinic of the institute. The patients were allocated randomly (flipping-coin simple randomization method) into an intervention group (n=50) and a control group (n=50). Patients in the intervention group received acupressure therapy along with pharmacological treatment. Patients in the control group did not receive acupressure therapy but continued their pharmacological treatment. Changes in pain (visual analog scale, VAS) and QOL (short-form 36-item health survey, SF-36) scores at baseline (A0), during training session (A1), follow-up at the 3rd month after training (A2) and follow-up at the 6th month after training session (A3) were collected and examined. Multiple regression analysis was used to check the relationship between pain and SF-36 domains. Results: The VAS score of participants in the intervention group decreased at A3 (P=0.001). Scores of physical functioning (PF), role limitations due to emotional problems (RE) and mental health (MH) of SF-36 in the intervention group improved more as compared with the control group. Patients in the intervention group with improvement in VAS (pain) score showed greater changes in mean scores of all domains of SF-36 from baseline (all P?0.05). Except bodily pain (BP), the other domains of SF-36 were negatively correlated with pain score. Conclusion: Acupressure therapy with pharmacological treatment can improve health-related QOL and pain among KOA patients.