The purpose of this study was to investigate the effect of various in vitro test conditions, on the release properties of theophylline (TP) from aminophylline (AP) matrices based on different hydroxypropylmethylcellulose (HPMC) ratio and viscosity grades. The General full factorial experimental design $3;{ imes};3;{ imes};3$ was used, based on three independent variables: applied in vitro test (X1), HPMC/drug ratio (X2) and polymer viscosity grade (X3). The drug release percent at 2h ($Y_{2h}$), 4h ($Y_{4h}$) and 8 h ($Y_{8h}$) and time for 50% of TP release from matrices ($Y_{T50%}$) were response variables. Three in vitro tests were used: Test 1 and Test 4 (Theophylline Extended-release Capsules, USP 30) and Half-change method. According to factorial design analyses, in vitro test was the most significant factor influencing mechanism and amount of drug release. For Half Change method erosion was the predominant mechanism indicating Case - II transport, while for Test 1 the release mechanism were followed by both diffusion and erosion. The lowest release exponent n values, obtained from Ritger-Pepass equation, for Test 4 indicate diffusion process inclining from Fickian diffusion to Anomalous transport. Therefore, it is in the stage of development, useful to consider the influence of various in vitro test conditions on the formulation, in order to choose an optimal test for the purpose of future drug release examination.