Toothpastes have a complex formulation and their different chemical and physical factors will influence their effectiveness against erosive tooth wear (ETW). We, therefore, investigated the effect of different desensitizing and/or anti-erosive toothpastes on initial enamel erosion and abrasion, and analysed how the interplay of their chemical and physical factors influences ETW. Human enamel specimens were submitted to 5 erosion-abrasion cycles using 9 different toothpastes and an artificial saliva group, and enamel surface loss (SL) was calculated. Chemical and physical factors (pH; presence of tin; calcium, phosphate and fluoride concentrations; % weight of solid particles; wettability; and particle size) of the toothpaste slurries were then analysed and associated with the amount of SL in a multivariate model. We observed that all desensitizing and/or anti-erosive toothpastes presented different degrees of SL. Besides pH and fluoride, all other chemical and physical factors were associated with SL. The results of this experiment indicate that enamel SL occurs independent of whether the toothpastes have a desensitizing or anti-erosive claim, and that lower SL is associated with the presence of tin, higher concentration of calcium and phosphate, higher % weight of solid particles, smaller particle size, and lower wettability.