Complementary treatments for osteoarthritis (OA) are sought by patients for symptomatic relief and to avoid the iatrogenic effects of non-steroidal anti-inflammatories. This systematic review evaluates the efficacy of the nutritional supplement Perna Canaliculus (green-lipped mussel, GLM) in the treatment of OA and substantially adds to previous work by focussing solely on GLM use in OA as well providing a re-analysis of the original trial data. Randomized or quasi-randomized controlled trials (comparative, placebo-controlled or crossover) were considered for inclusion from Cochrane Library, Medline, Embase, Amed, Cinahl, Scopus and NeLH databases where adults with OA of any joint were randomized to receive either GLM vs. placebo, no additional intervention (usual care), or an active intervention. The methodological quality of the trials was assessed using the JADAD scale. Four RCTs were included, three placebo controlled, the fourth a comparative trial of GLM lipid extract vs. stabilized powder extract. No RCTs comparing GLM to conventional treatment were identified. All four studies assessed GLM as an adjunctive treatment to conventional medication for a clinically relevant time in mild to moderate OA. All trials reported clinical benefits in the GLM treatment group but the findings from two studies cannot be included in this review because of possible un-blinding and inappropriate statistical analysis. The data from the two more rigorous trials, in conjunction with our re-analysis of original data suggests that GLM may be superior to placebo for the treatment of mild to moderate OA. As a credible biological mechanism exists for this treatment, further rigorous investigations are required to assess efficacy and optimal dosage.