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They have attracted attention due to their small size and molecular characteristics. Hydrophilic hallmark amino acids at framework region 2 (FR2) are key residues involved in the solubility of sdAbs. Nevertheless, previous studies reported that several sdAbs with human VH\u2010like hydrophobic hallmark residues were soluble in a monomeric state and suggested that solubility also depends on the amino acid sequences in the complementarity\u2010determining region. In this study, we obtained two sdAbs (sdAb A and B) with VH\u2010like hallmark residues and low solubility from an alpaca immune library. We introduced VHH\u2010like mutations (V37Y, G44E, L45R, W47L) into the hallmark residues in FR2 of both sdAb A and B. We were able to prepare sdAb A as a monomer without an additive in the buffer, but sdAb B was polydispersed when arginine was not added to the buffer. We also predicted the hydrophobicity of the sdAb B surface by spatial aggregation propensity calculations and identified W99 as the residue responsible for its low solubility. Subsequently, we obtained the sdAb B mutant as a monomer by introducing the W99A mutation. We characterized the engineered sdAbs using structural, physicochemical, and biophysical analyses and found that the solubility\u2010improved sdAbs retained their functionality. 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