The present invention provides a method of treating NPP1 deficiency or NPP1-associated disease such as idiopathic infantile arterial calcification (IIAC), pseudoxanthoma elasticum, vascular calcification in chronic kidney disease (VCCKD), insulin resistance, hypophosphatemic rickets, myocardial ischemia, joint calcification, angioid streaks, and ossification of the posterior longitudinal ligament of the spine. The present invention provides a method for treating tissue calcification by administering soluble NPP1 to produce a transient increase in serum pyrophosphate levels.