This study aimed to compare the efficacy of DIAGNOdent versus bitewing radiography and the international caries detection and assessment system (ICDAS) for detection of proximal and occlusal caries of primary teeth in presence/absence of dental plaque and moisture. In this diagnostic test study, 72 proximal and 75 occlusal surfaces of primary molars of children were examined for caries by using DIAGNOdent in three different conditions: (I) presence of dental plaque and moisture, (II) absence of dental plaque and presence of moisture, and (III) absence of dental plaque and moisture. The agreement, sensitivity, and specificity of DIAGNOdent were assessed and compared with bitewing radiography for detection of proximal caries and with ICDAS for detection of occlusal caries. Data were analyzed by the Friedman test, kappa coefficient of agreement, and McNemar test (alpha=0.05). DIAGNOdent results showed no significant difference in different conditions (P>0.05). The sensitivity of DIAGNOdent was not significantly different from that of bitewing radiography and ICDAS (P>0.05). The specificity of DIAGNOdent significantly decreased for detection of occlusal caries in presence of dental plaque (P<0.05). The highest agreement of DIAGNOdent with bitewing radiography and ICDAS was recorded in absence of dental plaque and presence of moisture. The DIAGNOdent values significantly decreased only for the occlusal surface after both plaque and moisture removal. Thus, presence of dental plaque and moisture may have no significant effect on clinical efficacy and performance of DIAGNOdent.