C57BL6 mice are melatonin deficient from birth and have been shown to develop scoliosis when rendered bipedal. Our previous work suggested that tamoxifen and trifluoperozine may change the natural course of scoliosis in a chicken model. The objective of this study was to analyze whether the incidence of scoliosis or the magnitude of curves may be decreased by the administration of pharmacological agents tamoxifen or trifluoperozine in a mice scoliosis model. Sixty female 3-week-old C57BL6 mice underwent amputations of forelimbs and tails. Available 57 mice were divided into three groups, Group-I received no medications whereas Groups II and III received 10 mg TMX and 10 mg TMX + 10 mg TFP per liter of daily water supply, respectively. PA scoliosis X-rays were obtained at 20th and 40th weeks. Deformities were compared for incidence and the severity of the curves as well as disease progression or regression. At 20th week, overall, upper thoracic (UT), lower thoracic (T), and lumbar (L) scoliosis rates were similar (P = 0.531; P = 0.209; P = 0.926; P = 0.215, respectively) but thoraco-lumbar (TL) scoliosis rate was higher inTMX group (P = 0.036). However, at 40th week, although TL and L rates were similar (P = 0.628, P = 0.080), overall rate as well as the rates of UT and T scoliosis of TMX group were significantly lower (P = 0.001, P = 0.011, P = 0.001, respectively). As for curve magnitudes, T mean Cobb angle at 20th week was significantly higher in the C group (14 +/- A 2.55) compared to TMX + TFP group (9 +/- A 2.708; P = 0.033); at 40th week, TL mean Cobb angle was lower in the TMX + TFP group (17.50 +/- A 3.45) compared to C (29.40 +/- A 5.98; P = 0.031); and TMX group had lower TL Cobb angles compared to C (8.67 +/- A 11.72) although not significant (P = 0.109). Double curve incidence at 40th week was significantly lower in TMX group compared to other groups (P = 0.001), triple curve incidence was lower in TMX + TFP and TMX groups, albeit not significant (P = 0.167). Between the 20th and 40th weeks, overall, double curve, and UT scoliosis rates showed an increase in C and TMX + TFP groups whereas TMX group showed a decline (P = 0.01, P = 0.002, P = 0.007, respectively). When specific regions were compared a similar significant difference was observed (P = 0.012 for upper thoracic; P = 0.018 for thoracic; P = 0.047 for thoraco-lumbar). This study has demonstrated that TMX is effective in changing the natural history of scoliotic deformities in C57BL6 mice model favorably.