This study evaluated the influence of the manipulation technique and polishing method on the flexural strength and cytotoxicity of acrylic resins. Two manipulation techniques and three polishing methods were used in the fabrication of acrylic plates that were divided into 6 groups (n=10). Groups MM, MC and MW: mass technique with mechanical polishing, chemical polishing and without polishing, respectively; and Groups SM, SC and SW: Saturation technique with mechanical polishing, chemical polishing and without polishing, respectively). Flexural strength was tested in a universal testing machine and the cytotoxicity assay used cell cultures (L-929) for periods of 24 h to 168 h. Flexural strength and cytotoxicity data were assessed using two-way and three-way ANOVA, respectively (a=0.05), followed by post hoc Bonferroni test for multiple comparisons. The effect of combinations of manipulation techniques and polishing methods on flexural strength showed significant differences only between Group SC and Groups MW, MM and MC (p<0.01). Cell viability ranged from 51% (3.9%) to 87,6% (3.2) in the 24-h time interval, and from 87.8% (5.0) to 95.7% (3.1%) in the 168-h time interval. With the increase of cell viability, from the third day (72 h), there was no significant difference among the groups, except between MM and SC (p<0.01) at 72 h. In conclusion, the manipulation technique and polishing method had more influence on the cytotoxicity than on flexural strength.