A combination of field mapping, geochemistry, and remote sensing methods has been employed to determine the extent of hydrothermal alteration and assess the potential for failure at the Santiaguito lava dome complex, Guatemala. The 90-year-old complex of four lava domes has only experienced relatively small and infrequent dome collapses in the past, which were associated with lava extrusion. However, existing evidence of an active hydrothermal system coupled with intense seasonal precipitation also presents ideal conditions for instability related to weakened clay-rich edifice rocks. Mapping of the Santiaguito dome complex identified structural features related to dome growth dynamics, potential areas of weakness related to erosion, and locations of fumarole fields. X-ray diffraction and backscattered electron images taken with scanning electron microscopy of dacite and ash samples collected from around fumaroles revealed only minor clay films, and little evidence of alteration. Mineral mapping using ASTER and Hyperion satellite images, however, suggest low-temperature (<150 °C) silicic alteration on erosional surfaces of the domes, but not the type of pervasive acid-sulfate alteration implicated in collapses of other altered edifices. To evaluate the possibility of internal alteration, we re-examined existing aqueous geochemical data from dome-fed hot springs. The data indicate significant water–rock interaction, but the Na–Mg–K geoindicator suggests only a short water residence time, and δ18O/δD ratios show only minor shifts from the meteoric water line with little precipitation of secondary (alteration) minerals. Based on available data, hydrothermal alteration on the dome complex appears to be restricted to surficial deposits of hydrous silica, but the study has highlighted, importantly, that the 1902 eruption crater headwall of Santa María does show more advanced argillic alteration. We also cannot rule out the possibility of advanced alteration within the dome complex interior that is not accessible to the methods used here. It may therefore be prudent to employ geophysical methods to make further assessments in the future.