OBJECTIVE : To determine the acquisition of Streptococcus mutans and dental caries experience in children with sickle cell anaemia (SCA) under various prophylactic therapies. METHODS : This study involved a total of 200 children who were divided into five groups comprising of 40 children each. Group SP included children who received prophylactic penicillin, Group SV who received pneumococcal vaccination, Group SPV who received both prophylactic penicillin and pneumococcal vaccination, Group SW who did not receive any prophylactic therapy and Group CC who were controls. Stimulated saliva samples from volunteers were collected and cultured in Mitis Salivarius Bacitracin (MSB) agar for estimation of Streptococcus mutans. Decayed, Missing, Filled (DMFT) index/decayed, exfoliated, and filled tooth (deft) index was used for assessment of dental caries. RESULTS : Group SP, Group SV, and Group SPV showed statistically significant difference in Streptococcus mutans count and dental caries experience in children when compared to Group SW and Group CC (p < 0.05) with the maximum reduction in Group SPV. No significant differences were observed in Group SW and Group CC. CONCLUSIONS : Reduction in the Streptococcus mutans acquisition and dental caries experience was seen in children with SCA who received prophylactic therapy with the least acquisition in combination therapy (Group SPV).