BACKGROUND: Osteoarthritis (OA) is the most common musculoskeletal disease in the world. OA is the result of an inflammatory and degenerative process affecting the entire joint. Osteoarthritis, especially involving the knee, has a relevant socioeconomic impact in terms of drugs, hospital admissions, work absences, and temporary or permanent invalidity. Therapy of knee osteoarthritis is based on pharmacological and nonpharmacological measures. METHODS: We conducted a systematic review of the studies published between 2002 and 2017 on spa therapy, mud-pack therapy, balneotherapy, and mud-bath therapy in the treatment of knee osteoarthritis in order to investigate the evidence of the efficacy of such treatment on pain, functional limitation, drug use, and quality of life. Overall, 35 studies were examined among which 12 were selected and included in the review if they are trial comparative. We have been able to illustrate the main results obtained in the individual studies and to elaborate these results in order to allow as much a unitary presentation as possible and hence an overall judgment. RESULTS: Because the studies we reviewed differed markedly from one another in terms of the methods used, we were unable to conduct a quantitative analysis (meta-analysis) of pooled data from the 12 studies. For the purposes of the present review, we reevaluated the results of the different studies using the same statistical method, Student's -test, which is used to compare the means of two frequency distributions. Among all the studies, the most relevant indexes used to measure effectiveness of spa therapy were improved including VAS, Lequesne, and WOMAC Score. CONCLUSIONS: The mud-pack therapy, balneotherapy, mud-bath therapy, and spa therapy have proved to be effective in the treatment and in the secondary prevention of knee osteoarthritis, by reducing pain, nonsteroidal anti-inflammatory drug consumption, and functional limitation and improving quality of life of affected patients.