© 2017, International League of Associations for Rheumatology (ILAR). Low-dose SoluMatrix diclofenac was developed to provide effective pain relief for osteoarthritis pain. We evaluated the effects of SoluMatrix diclofenac on health-related quality of life (HRQoL) measures in patients with osteoarthritis, hypothesizing that SoluMatrix-treated patients would experience significant improvement compared with placebo. In this 12-week, phase 3 randomized controlled trial, 305 patients with osteoarthritis of the hip or knee received SoluMatrix diclofenac 35 mg three times (TID) or twice (BID) daily or placebo. Measures included HRQoL, assessed by Short Form 36 (SF-36, version 2), and pain, stiffness, and physical function, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline and at week 12. Descriptive statistics were calculated for mean changes from baseline; inferential statistics compared treatment groups with placebo. SoluMatrix diclofenac 35 mg BID (6.2 [0.75]; P = 0.0048) or TID (6.6 [0.80]; P = 0.0014) produced large improvements in the SF-36 physical component summary (PCS) scores at week 12 (least squares mean change from baseline [SE]) compared with placebo (3.5 [0.78]). Minimum clinically important differences were observed in six out of eight SF-36 domains among patients in SoluMatrix diclofenac groups and five out of eight domains in the placebo group; treatment with SoluMatrix diclofenac 35 mg TID produced significant improvements (P ≤ 0.03) in five out of eight domains versus placebo. SoluMatrix diclofenac 35 mg TID significantly improved responses to 23 out of 24 questions in the WOMAC versus placebo (P ≤ 0.0334). Low-dose SoluMatrix diclofenac 35 mg TID and BID significantly improved HRQoL, pain, stiffness, and physical function in patients with osteoarthritis of the hip or knee.