Objective: Patients with systemic sclerosis (SSc) experience significant morbidity and mortality, therefore, the development of tests to aid its early diagnosis are very important. The aim of this pilot study was to assess the diagnostic value of novel optical non-invasive skin fluorescence spectroscopy (FS) and tissue oxygen saturation (TOS) viability measurements in patients with established SSc. Approach: Two groups were studied, comprising 14 SSc patients and nine healthy controls (93% and 73% females, respectively). FS and TOS measurements were collected from three body sites: the forearm, chest, and calf. Fluorescence intensities at wavelengths attributed to collagen, elastin, and L-tryptophan were computed, with adjustment for melanin, and a normalised combined fluorescence score (NCFS) was determined. Main results: The NCFS was significantly higher (p < 0.001) and the combined TOS significantly lower (p < 0.001) in the SSc group. TOS measurements alone showed good classification accuracy (95.7%) at separating SSc from healthy control participants, with some clustering of values close to the 50% oxygenation level in both groups. When the composition and viability measures were combined and modelled using binary logistic regression, excellent results for the sample were obtained following leave one out cross validation (100%). Significance: The results of this pilot study demonstrate the potential diagnostic utility of FS and TOS assessments in SSc patients and further work is now needed to validate these techniques prospectively in a larger group of SSc patients across the spectrum of the disease, and also patients with other types of vasculopathy and conditions that can cause skin fibrosis.