Human islet amyloid polypeptide (hIAPP or amylin) is a polypeptide hormone produced in the pancreatic β cells that plays a role in glycemic control. hIAPP is deficient in type 1 and type 2 diabetes and is a promising adjunct to insulin therapy. However, hIAPP rapidly forms amyloid and its strong tendency to aggregate limits its usefulness. The process of hIAPP amyloid formation is toxic to cultured -cells and islets, and islet amyloid formation in vivo has been linked to -cell death and to islet graft failure. An analog of hIAPP with reduced tendency to aggregate, denoted pramlintide (PM), has been approved for clinical applications, but suffers from poor solubility, particularly at physiological pH, and its unfavorable solubility profile prevents co-formulation with insulin. We describe a strategy to rationally design analogs of hIAPP with improved properties; key proline mutations are combined with substitutions that increase the net charge of the molecule. An H18R G24P I26P triple mutant and an H18R, A25P, S28P, S29P quadruple mutant are significantly more soluble at neutral pH than hIAPP or PM. They are non-amyloidogenic and are not toxic to INS -cells. The approach is not limited to these examples; additional analogs can be designed using this strategy. To illustrate this point we show that a S20R G24P I26P triple mutant and a H18R I26P double mutant are non-amyloidogenic and significantly more soluble than human IAPP or PM. These analogs and second generation derivatives are potential candidates for the co-formulation of IAPP with insulin and other polypeptides.