The area of Southern Serbia is the most undeveloped tourist area and is marginalized in relation to the total tourist traffic of Serbia. With the purpose of health tourism development, special attention in this paper is focused on five spas and four mountain tourist destinations of South Serbia. The interaction of climatic elements is key for outdoor tourist activities, thus the potential of health tourism is presented through the results of the tourism climate comfort index (TCCI). According to TCCI values calculated for one climatological period 1991–2020, the spa tourist destinations of South Serbia are generally favorable during May, June and September. Four studied mountain destinations have favorable TCCI values generally during June, July and August. Spatio-temporal analysis utilizing ESRI ArcMap software showed that the most favorable conditions for health tourism development occur during spring and autumn for spas (May and June) and during summer for mountain destinations (July and August), which coincides with the ideal TCCI values. MatLab software through linear regression showed that in the period of 2010–2020, a negative tendency of tourists’ number in Vranjska banja spa and Niška banja spa is noticed, and a positive tendency for Prolom banja spa and Sijarinska banja spa. The paper also highlights the perspectives of other tourism forms of development in South Serbia.
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