Three distinct temporal phases of synaptic facilitation (short-, intermediate-, and long-term) are induced by serotonin (5-HT) at sensory (SN) to motor (MN) synapses in Aplysia. Here, we characterize two mechanistically distinct forms of intermediate-term facilitation (ITF) at tail SN-MN synapses. One form, activity-independent ITF, is produced by five spaced pulses of 5-HT in the absence of SN activity. Its induction requires protein synthesis, and its expression requires persistent activation of PKA but not PKC. The other form, activity-dependent ITF, is produced by a single pulse of 5-HT coincident with SN activation. Its induction does not require protein synthesis, and its expression requires persistent activation of PKC but not PKA. These results demonstrate that SN-MN synapses can exhibit two distinct forms of ITF that are mediated by parallel molecular pathways.