Safflower (Carthamus tinctoriusL.) is a promising oilseed crop for cultivation in central Southern Italy due to its high tolerance to drought and salinity stress and appreciable seed and oil yields. The genetic diversity of cultivars and climate factors can affect fatty acid composition and yield traits. This study aimed to assess the effects of genotype and climate conditions on the productive performance of eight high oleic safflower genotypes under rainfed conditions in Sicily (Italy). These genotypes were compared to the Montola 2000 cultivar, which was used as a reference. Tests were carried out during the growing seasons of 2014–2015 and 2015–2016. The experimental design was a randomized complete block design with three replications. Morphological and yield components were significantly affected by genotype while the year had a significant effect on plant height only. In general, CTI 17 produced the highest seed yield (1.40 t ha−1) and oil yield (0.58 t ha−1). The seed oil content was found on 40.2% of dry matter, on average. The “genotype” factor significantly affected oil content and fatty acid composition. Oleic acid content was on average 66.1% and did not vary greatly over the two growing seasons. The above- and belowground plant parts showed the highest carbon content and the lowest nitrogen content as a percentage of dry matter. The results indicate that, under rainfed conditions, yield parameters of high oleic safflower genotypes can be profitable in southern Italy though significantly dependent upon genotype.