The current scientific literature relevant to the use of prolotherapy for osteoarthritis, low back pain, and other musculoskeletal conditions was reviewed and critically analyzed to determine a clinical effect. Three randomized, controlled studies were found studying the use of dextrose/glycerine/phenol prolotherapy for chronic low back pain; however, they were inconclusive due to the lack of adequate controls, heterogeneity in patient diagnoses, and variations in solutions injected. Two randomized, controlled studies were found that provide some evidence supporting the use of 10% dextrose prolotherapy for osteoarthritis. The sample size of the study (n = 13) involving osteoarthritic thumbs and fingers may have been too small to be strongly conclusive; however, it provides preliminary data to support future studies. Two studies involving osteoarthritic knees report an improvement in anterior cruciate ligament laxity; however, they did not have control groups for comparison. Only case reports were found supporting the pursuit of controlled clinical studies of prolotherapy for chronic neck pain. On the basis of the scarce body of literature critically reviewed to date, the clinical efficacy of prolotherapy in treating osteoarthritis, low back pain, and other musculoskeletal conditions remains inconclusive.