Make sure your comic is funny. This is more important than anything else. A comic strip that has amateurish artwork but good jokes will always succeed more than one with great art that isn't funny.
Create characters with different personalities, making it easy to draw conflict among one another. You'll definitely want a character who's rude, selfish and sarcastic and a kind, good-natured character to be the other's foil.
Add new characters whenever you can think them up. You never know who you may create that readers may end up loving. Someone who you thought would only appear for a week of strips may become a favorite recurring character.
Push the boundaries. Challenge the comics' censorship standards, which many say are still stuck in the 50s. Take up controversial issues and make them funny. You'll drive your syndicate crazy but will win a loyal fan base.
Keep track of current events. Then write them into your comics. People will surely love your comic if you can take serious issues going on today and make them laugh about it.