The present study analyzes the accuracy of the clinical diagnosis of X-linked ichthyosis (XLI) vs ichthyosis vulgaris (IV), in a sample of Mexican patients. The study was double blind, using steroid sulfatase (STS) activity as the golden standard. Twenty male patients were included; 16 corresponded to XLI and 4 to IV. The clinical diagnosis was correct in 9 of the 16 XLI cases (56%) and in 2 of the 4 IV cases (50%). Some clinical findings in XLI, such as cryptorchidism in patients and delayed labor in their mothers, were important features for diagnosis. Statistical analysis of the results showed: among physicians (n = 2) Kappa value 0.50, specific concordance 0.40, and absolute concordance 0.75; other values were sensibility 0.56, specificity 0.50, positive predictive value 0.82, negative predictive value 0.22, accuracy 0.55, prevalence 0.80. In conclusion, the differential diagnosis of XLI and IV is very difficult, and we consider that this is not explained either by personal skills or by other conditions. It could be attributed to the similarities in skin manifestations of these two diseases. The performance of the STS assay is imperative in order to correctly diagnose the disease and offer adequate genetic counseling.