Osteoarthritis (OA) is a disorder involving the deterioration of articular cartilage and underlying bone and is associated with symptoms of pain and disability. In military personnel, the incidence of OA has increased between 2000 and 2012 and was the first or second leading cause of medical separations in this period. It has been suggested that consumption of chondroitin sulfate (CS) may reduce the pain and joint deterioration associated with OA. This article reports on a systematic review and meta-analysis of the effectiveness of CS on reducing OA-related pain and joint deterioration. PubMed and Ovid Embase databases and other sources were searched to find randomized, double-blind, placebo-controlled trials on the effects of orally consumed CS on pain and/or joint structure. The outcome measure was the standardized mean difference (SMD) which was the improvement in the placebo groups minus the improvement in the CS groups divided by the pooled standard deviation. There were 18 trials meeting the review criteria for pain with SMD -0.41, 95% confidence interval (95% CI) -0.57 to -0.25 (negative SMD favors CS). Six studies met the review criteria for joint space narrowing with SMD -0.30, 95% CI -0.61 to +0.00. Two studies meet the review criteria for cartilage volume with SMD -0.11, 95% CI -0.48 to +0.26. Larger dosages (1200mg/d) had greater pain reduction efficacy than lower dosages (≤ 1000mg/d). These data suggest that CS has small to moderate effectiveness in reducing OA-related pain but minimal effects on joint space narrowing and no effect on cartilage volume. It is important that clinicians recommend pharmaceutical-grade CS to their patients due to the variability in the amount of CS in dietary supplements purporting to contain CS.