Objectives: In a mouse model, aldehyde dehydrogenase 2 (ALDH2) knockout resulted in lower bone mineral density; however, higher parathyroid hormone receptor expression than wild-type mice. This study aimed to investigate whether ALDH2 polymorphisms influence efficacy of intermittent parathyroid hormone therapy and bone mineral density changes in humans. Methods: Eighty-two patients with primary osteoporosis treated with parathyroid hormone for > 1 year were divided into wild-type ALDH2 (ALDH2*1) and variant (ALDH2*2) groups. Bone mineral densities were measured by dual-energy X-ray absorptiometry. Changes in bone mineral density, treatment response, bone turnover markers, and new fracture incidence were evaluated. Furthermore, bone mineral density was analyzed using a mixed-effects model. Results: Femoral neck bone mineral density increased by 1.0 ± 7.4% in the ALDH2*1 group and 4.3 ± 8.1% in the ALDH2*2 group (P < 0.05), whereas lumbar spine bone mineral density increased by 5.7 ± 8.2% and 9.4 ± 9.1% without significance. Treatment success rates were higher in ALDH2*2 group (femoral neck 38.7%, lumbar spine 68.8%) compared with ALDH2*1 (16.3%, 51.0%). Statistical significance was observed only at the femoral neck. Bone turnover markers and fracture incidence were comparable between groups. Mixed-effects analysis adjusting for confounders showed a significant ALDH2 genotype × duration interaction for femoral neck, indicating genotype-related differences in the rate of bone mineral density increase over time. For lumbar spine, the genotype main effect was significant, whereas the interaction was not. Conclusions These findings suggest that ALDH2 polymorphisms may influence the therapeutic response to PTH treatment and highlight the need for larger future studies.